Archives of Toxicology

, Volume 88, Issue 12, pp 2099–2133 | Cite as

SEURAT-1 liver gold reference compounds: a mechanism-based review

  • Paul Jennings
  • Michael Schwarz
  • Brigitte Landesmann
  • Silvia Maggioni
  • Marina Goumenou
  • David Bower
  • Martin O. Leonard
  • Jeffrey S. Wiseman
Review Article

Abstract

There is an urgent need for the development of alternative methods to replace animal testing for the prediction of repeat dose chemical toxicity. To address this need, the European Commission and Cosmetics Europe have jointly funded a research program for ‘Safety Evaluation Ultimately Replacing Animal Testing.’ The goal of this program was the development of in vitro cellular systems and associated computational capabilities for the prediction of hepatic, cardiac, renal, neuronal, muscle, and skin toxicities. An essential component of this effort is the choice of appropriate reference compounds that can be used in the development and validation of assays. In this review, we focus on the selection of reference compounds for liver pathologies in the broad categories of cytotoxicity and lipid disorders. Mitochondrial impairment, oxidative stress, and apoptosis are considered under the category of cytotoxicity, while steatosis, cholestasis, and phospholipidosis are considered under the category of lipid dysregulation. We focused on four compound classes capable of initiating such events, i.e., chemically reactive compounds, compounds with specific cellular targets, compounds that modulate lipid regulatory networks, and compounds that disrupt the plasma membrane. We describe the molecular mechanisms of these compounds and the cellular response networks which they elicit. This information will be helpful to both improve our understanding of mode of action and help in the selection of appropriate mechanistic biomarkers, allowing us to progress the development of animal-free models with improved predictivity to the human situation.

Keywords

SEURAT-1 Hepatotoxin MIE MoA Nuclear receptor Stress response 

References

  1. Adedoyin A, Aarons L, Houston JB (1993) Time-dependent disposition of beta-naphthoflavone in the rat. Pharm Res 10(1):35–43PubMedGoogle Scholar
  2. Agarwal AR, Yin F, Cadenas E (2013) Metabolic shift in lung alveolar cell mitochondria following acrolein exposure. Am J Physiol Lung Cell Mol Physiol 305(10):L764–L773. doi:10.1152/ajplung.00165.2013 PubMedGoogle Scholar
  3. Albano E, Rundgren M, Harvison PJ, Nelson SD, Moldeus P (1985) Mechanisms of N-acetyl-p-benzoquinone imine cytotoxicity. Mol Pharmacol 28(3):306–311PubMedGoogle Scholar
  4. Albrecht B, Weidhase R, Stock M, Weidhase RA (1991) In vivo utilization of N-(phosphonomethyl)-anilines and related substances by Pseudomonas spec. GS. J Basic Microbiol 31(6):403–411PubMedGoogle Scholar
  5. Anderson N, Borlak J (2006) Drug-induced phospholipidosis. FEBS Lett 580(23):5533–5540. doi:10.1016/j.febslet.2006.08.061 PubMedGoogle Scholar
  6. Andersson BS, Rundgren M, Nelson SD, Harder S (1990) N-acetyl-p-benzoquinone imine-induced changes in the energy metabolism in hepatocytes. Chem Biol Interact 75(2):201–211PubMedGoogle Scholar
  7. Anestal K, Prast-Nielsen S, Cenas N, Arner ES (2008) Cell death by SecTRAPs: thioredoxin reductase as a prooxidant killer of cells. PLoS ONE 3(4):e1846. doi:10.1371/journal.pone.0001846 PubMedCentralPubMedGoogle Scholar
  8. Aninat C, Piton A, Glaise D et al (2006) Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos 34(1):75–83. doi:10.1124/dmd.105.006759 PubMedGoogle Scholar
  9. Antherieu S, Rogue A, Fromenty B, Guillouzo A, Robin MA (2011) Induction of vesicular steatosis by amiodarone and tetracycline is associated with up-regulation of lipogenic genes in HepaRG cells. Hepatology 53(6):1895–1905. doi:10.1002/hep.24290 PubMedGoogle Scholar
  10. Azzaoui K, Hamon J, Faller B et al (2007) Modeling promiscuity based on in vitro safety pharmacology profiling data. ChemMedChem 2(6):874–880. doi:10.1002/cmdc.200700036 PubMedGoogle Scholar
  11. Badr MZ, Belinsky SA, Kauffman FC, Thurman RG (1986) Mechanism of hepatotoxicity to periportal regions of the liver lobule due to allyl alcohol: role of oxygen and lipid peroxidation. J Pharmacol Exp Ther 238(3):1138–1142PubMedGoogle Scholar
  12. Bajt ML, Knight TR, Lemasters JJ, Jaeschke H (2004) Acetaminophen-induced oxidant stress and cell injury in cultured mouse hepatocytes: protection by N-acetyl cysteine. Toxicol Sci 80(2):343–349. doi:10.1093/toxsci/kfh151 PubMedGoogle Scholar
  13. Balijepalli S, Boyd MR, Ravindranath V (1999) Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation. Neuropharmacology 38(4):567–577PubMedGoogle Scholar
  14. Bedard LL, Massey TE (2006) Aflatoxin B1-induced DNA damage and its repair. Cancer Lett 241(2):174–183. doi:10.1016/j.canlet.2005.11.018 PubMedGoogle Scholar
  15. Beischlag TV, Luis Morales J, Hollingshead BD, Perdew GH (2008) The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 18(3):207–250PubMedCentralPubMedGoogle Scholar
  16. Birnbaum LS, Tuomisto J (2000) Non-carcinogenic effects of TCDD in animals. Food Addit Contam 17(4):275–288. doi:10.1080/026520300283351 PubMedGoogle Scholar
  17. Boergesen M, Pedersen TA, Gross B et al (2012) Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor alpha in mouse liver reveals extensive sharing of binding sites. Mol Cell Biol 32(4):852–867. doi:10.1128/MCB.06175-11 PubMedCentralPubMedGoogle Scholar
  18. Bolt HM, Remmer H (1976) Implication of rifampicin-quinone in the irreversible binding of rifampicin to macromolecules. Xenobiotica 6(1):21–32. doi:10.3109/00498257609151608 PubMedGoogle Scholar
  19. Boobis AR, Doe JE, Heinrich-Hirsch B et al. (2008) IPCS framework for analyzing the relevance of a noncancer mode of action for humans. Crit Rev Toxicol 38(2):87–96. doi:10.1080/10408440701749421 PubMedGoogle Scholar
  20. Bongard RD, Lindemer BJ, Krenz GS, Merker MP (2009) Preferential utilization of NADPH as the endogenous electron donor for NAD(P)H:quinone oxidoreductase 1 (NQO1) in intact pulmonary arterial endothelial cells. Free Radical Biol Med 46(1):25–32. doi:10.1016/j.freeradbiomed.2008.09.007 Google Scholar
  21. Boobis AR, Tee LB, Hampden CE, Davies DS (1986) Freshly isolated hepatocytes as a model for studying the toxicity of paracetamol. Food Chem Toxicol 24(6–7):731–736PubMedGoogle Scholar
  22. Brand MD, Nicholls DG (2011) Assessing mitochondrial dysfunction in cells. Biochem J 435(2):297–312. doi:10.1042/BJ20110162 PubMedCentralPubMedGoogle Scholar
  23. Bresgen N, Karlhuber G, Krizbai I, Bauer H, Bauer HC, Eckl PM (2003) Oxidative stress in cultured cerebral endothelial cells induces chromosomal aberrations, micronuclei, and apoptosis. J Neurosci Res 72(3):327–333. doi:10.1002/jnr.10582 PubMedGoogle Scholar
  24. Brown PJ, Stuart LW, Hurley KP et al (2001) Identification of a subtype selective human PPARalpha agonist through parallel-array synthesis. Bioorg Med Chem Lett 11(9):1225–1227PubMedGoogle Scholar
  25. Bruno S, Maisonneuve P, Castellana P et al (2005) Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ 330(7497):932. doi:10.1136/bmj.38391.663287.E0 PubMedCentralPubMedGoogle Scholar
  26. Burcham PC, Harman AW (1991) Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes. J Biol Chem 266(8):5049–5054PubMedGoogle Scholar
  27. Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ (2002) The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology 123(5):1649–1658PubMedGoogle Scholar
  28. Cai Q, Bensen M, Greene R, Kirchner J (2000) Tamoxifen-induced transient multifocal hepatic fatty infiltration. Am J Gastroenterol 95(1):277–279. doi:10.1111/j.1572-0241.2000.01708.x PubMedGoogle Scholar
  29. Cardoso CM, Custodio JB, Almeida LM, Moreno AJ (2001) Mechanisms of the deleterious effects of tamoxifen on mitochondrial respiration rate and phosphorylation efficiency. Toxicol Appl Pharmacol 176(3):145–152. doi:10.1006/taap.2001.9265 PubMedGoogle Scholar
  30. Carey MC, Hirom PC, Small DM (1976) A study of the physicochemical interactions between biliary lipids and chlorpromazine hydrochloride. Bile-salt precipitation as a mechanism of phenothiazine-induced bile secretory failure. Biochem J 153(3):519–531PubMedCentralPubMedGoogle Scholar
  31. Caron S, Huaman Samanez C, Dehondt H et al (2013) Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes. Mol Cell Biol 33(11):2202–2211. doi:10.1128/MCB.01004-12 PubMedCentralPubMedGoogle Scholar
  32. Carthew P, Lee PN, Edwards RE, Heydon RT, Nolan BM, Martin EA (2001) Cumulative exposure to tamoxifen: DNA adducts and liver cancer in the rat. Arch Toxicol 75(6):375–380PubMedGoogle Scholar
  33. Cha JY, Repa JJ (2007) The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J Biol Chem 282(1):743–751. doi:10.1074/jbc.M605023200 PubMedGoogle Scholar
  34. Chan ES, Cronstein BN (2010) Adenosine in fibrosis. Mod Rheumatol 20(2):114–122. doi:10.1007/s10165-009-0251-4 PubMedCentralPubMedGoogle Scholar
  35. Chan WK, Yao G, Gu YZ, Bradfield CA (1999) Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. Demonstration of competition and compensation. J Biol Chem 274(17):12115–12123PubMedGoogle Scholar
  36. Chan ES, Montesinos MC, Fernandez P et al (2006) Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol 148(8):1144–1155. doi:10.1038/sj.bjp.0706812 PubMedCentralPubMedGoogle Scholar
  37. Chateauvieux S, Morceau F, Dicato M, Diederich M (2010) Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. doi:10.1155/2010/479364
  38. Chatelain P, Ferreira J, Laruel R, Ruysschaert JM (1986) Amiodarone induced modifications of the phospholipid physical state. A fluorescence polarization study. Biochem Pharmacol 35(18):3007–3013PubMedGoogle Scholar
  39. Chatelain P, Laruel R, Vic P, Brotelle R (1989) Differential effects of amiodarone and propranolol on lipid dynamics and enzymatic activities in cardiac sarcolemmal membranes. Biochem Pharmacol 38(8):1231–1239PubMedGoogle Scholar
  40. Chaudhuri S, McCullough SS, Hennings L et al (2011) Acetaminophen hepatotoxicity and HIF-1alpha induction in acetaminophen toxicity in mice occurs without hypoxia. Toxicol Appl Pharmacol 252(3):211–220. doi:10.1016/j.taap.2011.02.005 PubMedCentralPubMedGoogle Scholar
  41. Chen J, Raymond K (2006) Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor. Ann Clin Microbiol Antimicrob 5:3. doi:10.1186/1476-0711-5-3 PubMedCentralPubMedGoogle Scholar
  42. Chen Q, Stevens JL (1991) Inhibition of iodoacetamide and t-butylhydroperoxide toxicity in LLC-PK1 cells by antioxidants: a role for lipid peroxidation in alkylation induced cytotoxicity. Arch Biochem Biophys 284(2):422–430PubMedGoogle Scholar
  43. Chen W, Shockcor JP, Tonge R, Hunter A, Gartner C, Nelson SD (1999) Protein and nonprotein cysteinyl thiol modification by N-acetyl-p-benzoquinone imine via a novel ipso adduct. Biochemistry 38(25):8159–8166. doi:10.1021/bi990125k PubMedGoogle Scholar
  44. Cheng Q, Antholine WE, Myers JM, Kalyanaraman B, Arner ES, Myers CR (2010) The selenium-independent inherent pro-oxidant NADPH oxidase activity of mammalian thioredoxin reductase and its selenium-dependent direct peroxidase activities. J Biol Chem 285(28):21708–21723. doi:10.1074/jbc.M110.117259 PubMedCentralPubMedGoogle Scholar
  45. Chinopoulos C, Gerencser AA, Mandi M et al (2010) Forward operation of adenine nucleotide translocase during F0F1-ATPase reversal: critical role of matrix substrate-level phosphorylation. FASEB J 24(7):2405–2416. doi:10.1096/fj.09-149898 PubMedCentralPubMedGoogle Scholar
  46. Clarke AE, Denborough MA (1971) Interaction of chlorpromazine with bile. Clin Chem 17(10):998–1001PubMedGoogle Scholar
  47. Coen M, Lenz EM, Nicholson JK, Wilson ID, Pognan F, Lindon JC (2003) An integrated metabonomic investigation of acetaminophen toxicity in the mouse using NMR spectroscopy. Chem Res Toxicol 16(3):295–303. doi:10.1021/tx0256127 PubMedGoogle Scholar
  48. Cole LK, Jacobs RL, Vance DE (2010) Tamoxifen induces triacylglycerol accumulation in the mouse liver by activation of fatty acid synthesis. Hepatology 52(4):1258–1265. doi:10.1002/hep.23813 PubMedGoogle Scholar
  49. Coles B, Wilson I, Wardman P, Hinson JA, Nelson SD, Ketterer B (1988) The spontaneous and enzymatic reaction of N-acetyl-p-benzoquinonimine with glutathione: a stopped-flow kinetic study. Arch Biochem Biophys 264(1):253–260PubMedGoogle Scholar
  50. Collins JL, Fivush AM, Watson MA et al (2002) Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 45(10):1963–1966PubMedGoogle Scholar
  51. Copple IM, Goldring CE, Jenkins RE et al (2008) The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system. Hepatology 48(4):1292–1301. doi:10.1002/hep.22472 PubMedGoogle Scholar
  52. Coskun U, Toruner FB, Gunel N (2002) Tamoxifen therapy and hepatic steatosis. Neoplasma 49(1):61–64PubMedGoogle Scholar
  53. Custodio JB, Almeida LM, Madeira VM (1993) The anticancer drug tamoxifen induces changes in the physical properties of model and native membranes. Biochim Biophys Acta 1150(2):123–129PubMedGoogle Scholar
  54. Dahlin DC, Miwa GT, Lu AY, Nelson SD (1984) N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 81(5):1327–1331PubMedCentralPubMedGoogle Scholar
  55. Dang TN, Arseneault M, Ramassamy C (2011) Regulation of redox-sensitive signaling pathways in rat primary astrocytes following acrolein exposure. J Alzheimers Dis 25(2):263–277. doi:10.3233/JAD-2011-102094 PubMedGoogle Scholar
  56. Dastoor Z, Dreyer JL (2001) Potential role of nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase in apoptosis and oxidative stress. J Cell Sci 114(Pt 9):1643–1653PubMedGoogle Scholar
  57. Daston GP (2013) Chemical structure-based toxicity databases: insight into molecular initiating events. In: Schwarz M, Gocht T (eds) SEURAT-1 annual book: Towards the replacement of in vivo repeated dose systemic toxicity testing, vol 3. (self-publishing), Paris, FranceGoogle Scholar
  58. Dayan F, Bilton RL, Laferriere J et al (2009) Activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway. J Cell Physiol 218(1):167–174. doi:10.1002/jcp.21584 PubMedGoogle Scholar
  59. Dieudonne MN, Leneveu MC, Giudicelli Y, Pecquery R (2004) Evidence for functional estrogen receptors alpha and beta in human adipose cells: regional specificities and regulation by estrogens. Am J Physiol Cell Physiol 286(3):C655–C661. doi:10.1152/ajpcell.00321.2003 PubMedGoogle Scholar
  60. DiNatale BC, Smith K, John K, Krishnegowda G, Amin SG, Perdew GH (2012) Ah receptor antagonism represses head and neck tumor cell aggressive phenotype. Mol Cancer Res 10(10):1369–1379. doi:10.1158/1541-7786.MCR-12-0216 PubMedCentralPubMedGoogle Scholar
  61. Dodds ML, Kargacin ME, Kargacin GJ (2001) Effects of anti-oestrogens and beta-estradiol on calcium uptake by cardiac sarcoplasmic reticulum. Br J Pharmacol 132(7):1374–1382. doi:10.1038/sj.bjp.0703924 PubMedCentralPubMedGoogle Scholar
  62. Donato MT, Martinez-Romero A, Jimenez N et al (2009) Cytometric analysis for drug-induced steatosis in HepG2 cells. Chem Biol Interact 181(3):417–423. doi:10.1016/j.cbi.2009.07.019 PubMedGoogle Scholar
  63. Dranka BP, Hill BG, Darley-Usmar VM (2010) Mitochondrial reserve capacity in endothelial cells: the impact of nitric oxide and reactive oxygen species. Free Radical Biol Med 48(7):905–914. doi:10.1016/j.freeradbiomed.2010.01.015 Google Scholar
  64. Drose S, Brandt U (2008) The mechanism of mitochondrial superoxide production by the cytochrome bc1 complex. J Biol Chem 283(31):21649–21654. doi:10.1074/jbc.M803236200 PubMedGoogle Scholar
  65. Dypbukt JM, Ankarcrona M, Burkitt M et al (1994) Different prooxidant levels stimulate growth, trigger apoptosis, or produce necrosis of insulin-secreting RINm5F cells. The role of intracellular polyamines. J Biol Chem 269(48):30553–30560PubMedGoogle Scholar
  66. Eggler AL, Liu G, Pezzuto JM, van Breemen RB, Mesecar AD (2005) Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc Natl Acad Sci USA 102(29):10070–10075. doi:10.1073/pnas.0502402102 PubMedCentralPubMedGoogle Scholar
  67. Eggler AL, Luo Y, van Breemen RB, Mesecar AD (2007) Identification of the highly reactive cysteine 151 in the chemopreventive agent-sensor Keap1 protein is method-dependent. Chem Res Toxicol 20(12):1878–1884. doi:10.1021/tx700217c PubMedGoogle Scholar
  68. Eick GN, Colucci JK, Harms MJ, Ortlund EA, Thornton JW (2012) Evolution of minimal specificity and promiscuity in steroid hormone receptors. PLoS Genet 8(11):e1003072. doi:10.1371/journal.pgen.1003072 PubMedCentralPubMedGoogle Scholar
  69. Eloranta JJ, Kullak-Ublick GA (2005) Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch Biochem Biophys 433(2):397–412. doi:10.1016/j.abb.2004.09.019 PubMedGoogle Scholar
  70. Enomoto A, Itoh K, Nagayoshi E et al (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 59(1):169–177PubMedGoogle Scholar
  71. Ernst MC, Sinal CJ, Pollak PT (2010) Influence of peroxisome proliferator-activated receptor-alpha (PPARalpha) activity on adverse effects associated with amiodarone exposure in mice. Pharmacol Res 62(5):408–415. doi:10.1016/j.phrs.2010.07.004 PubMedGoogle Scholar
  72. Etienne MC, Milano G, Fischel JL et al (1989) Tamoxifen metabolism: pharmacokinetic and in vitro study. Br J Cancer 60(1):30–35PubMedCentralPubMedGoogle Scholar
  73. Evans N, Rabin BR (1968) Inhibition studies on liver alcohol dehydrogenase. Eur J Biochem 4(4):548–554PubMedGoogle Scholar
  74. Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA (2004) Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 17(1):3–16. doi:10.1021/tx034170b PubMedGoogle Scholar
  75. Fattinger K, Funk C, Pantze M et al (2001) The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 69(4):223–231. doi:10.1067/mcp.2001.114667 PubMedGoogle Scholar
  76. Fenniche S, Maalej S, Fekih L, Hassene H, Belhabib D, Megdiche ML (2003) Manifestations of rifampicin-induced hypersensitivity. Presse Med 32(25):1167–1169PubMedGoogle Scholar
  77. Fenselau A (1970) Nicotinamide adenine dinucleotide as an active site director in glyceraldehyde 3-phosphate dehydrogenase modification. J Biol Chem 245(6):1239–1246PubMedGoogle Scholar
  78. Fernandez-Alvarez A, Alvarez MS, Gonzalez R, Cucarella C, Muntane J, Casado M (2011) Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem 286(24):21466–21477. doi:10.1074/jbc.M110.209973 PubMedCentralPubMedGoogle Scholar
  79. Floreani M, Carpenedo F (1995) Metabolism of simple quinones in guinea pig and rat cardiac tissue. Gen Pharmacol 26(8):1757–1764PubMedGoogle Scholar
  80. Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 94(9):4312–4317PubMedCentralPubMedGoogle Scholar
  81. Foryst-Ludwig A, Clemenz M, Hohmann S et al (2008) Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genet 4(6):e1000108. doi:10.1371/journal.pgen.1000108 PubMedCentralPubMedGoogle Scholar
  82. Fromenty B, Pessayre D (1995) Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol Ther 67(1):101–154PubMedGoogle Scholar
  83. Fromenty B, Fisch C, Berson A, Letteron P, Larrey D, Pessayre D (1990) Dual effect of amiodarone on mitochondrial respiration. Initial protonophoric uncoupling effect followed by inhibition of the respiratory chain at the levels of complex I and complex II. J Pharmacol Exp Ther 255(3):1377–1384PubMedGoogle Scholar
  84. Fromenty B, Letteron P, Fisch C, Berson A, Deschamps D, Pessayre D (1993) Evaluation of human blood lymphocytes as a model to study the effects of drugs on human mitochondria. Effects of low concentrations of amiodarone on fatty acid oxidation, ATP levels and cell survival. Biochem Pharmacol 46(3):421–432PubMedGoogle Scholar
  85. Fuchs M (2012) Non-alcoholic Fatty liver disease: the bile acid-activated farnesoid x receptor as an emerging treatment target. J Lipids 2012:934396. doi:10.1155/2012/934396 PubMedCentralPubMedGoogle Scholar
  86. Furuno T, Kanno T, Arita K et al (2001) Roles of long chain fatty acids and carnitine in mitochondrial membrane permeability transition. Biochem Pharmacol 62(8):1037–1046PubMedGoogle Scholar
  87. Gant TW, Rao DN, Mason RP, Cohen GM (1988) Redox cycling and sulphydryl arylation; their relative importance in the mechanism of quinone cytotoxicity to isolated hepatocytes. Chem Biol Interact 65(2):157–173PubMedGoogle Scholar
  88. Gavrilova O, Haluzik M, Matsusue K et al (2003) Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 278(36):34268–34276. doi:10.1074/jbc.M300043200 PubMedGoogle Scholar
  89. Gerets HH, Tilmant K, Gerin B et al (2012) Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. Cell Biol Toxicol 28(2):69–87. doi:10.1007/s10565-011-9208-4 PubMedCentralPubMedGoogle Scholar
  90. Glatz JF, Luiken JJ, Bonen A (2010) Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol Rev 90(1):367–417. doi:10.1152/physrev.00003.2009 PubMedGoogle Scholar
  91. Goldring CE, Kitteringham NR, Elsby R et al (2004) Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice. Hepatology 39(5):1267–1276. doi:10.1002/hep.20183 PubMedGoogle Scholar
  92. Gomez-Lechon MJ, Tolosa L, Castell JV, Donato MT (2010) Mechanism-based selection of compounds for the development of innovative in vitro approaches to hepatotoxicity studies in the LIINTOP project. Toxicol In Vitro Int J Publ Assoc BIBRA 24(7):1879–1889. doi:10.1016/j.tiv.2010.07.018 Google Scholar
  93. Gonzalez-Rothi RJ, Zander DS, Ros PR (1995) Fluoxetine hydrochloride (Prozac)-induced pulmonary disease. Chest 107(6):1763–1765PubMedGoogle Scholar
  94. Goodwin B, Jones SA, Price RR et al (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6(3):517–526PubMedGoogle Scholar
  95. Goodwin B, Watson MA, Kim H, Miao J, Kemper JK, Kliewer SA (2003) Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alpha. Mol Endocrinol 17(3):386–394. doi:10.1210/me.2002-0246 PubMedGoogle Scholar
  96. Gottlicher M, Minucci S, Zhu P et al (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20(24):6969–6978. doi:10.1093/emboj/20.24.6969 PubMedCentralPubMedGoogle Scholar
  97. Grefhorst A, Elzinga BM, Voshol PJ et al (2002) Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem 277(37):34182–34190. doi:10.1074/jbc.M204887200 PubMedGoogle Scholar
  98. Grover GJ, Atwal KS, Sleph PG et al (2004) Excessive ATP hydrolysis in ischemic myocardium by mitochondrial F1F0-ATPase: effect of selective pharmacological inhibition of mitochondrial ATPase hydrolase activity. Am J Physiol Heart Circ Physiol 287(4):H1747–H1755. doi:10.1152/ajpheart.01019.2003 PubMedGoogle Scholar
  99. Gudbrandsen OA, Rost TH, Berge RK (2006) Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver. J Lipid Res 47(10):2223–2232. doi:10.1194/jlr.M600148-JLR200 PubMedGoogle Scholar
  100. Guengerich FP, Arneson KO, Williams KM, Deng Z, Harris TM (2002) Reaction of aflatoxin B(1) oxidation products with lysine. Chem Res Toxicol 15(6):780–792PubMedGoogle Scholar
  101. Haarmann-Stemmann T, Abel J, Fritsche E, Krutmann J (2012) The AhR-Nrf2 pathway in keratinocytes: on the road to chemoprevention? J Invest Dermatol 132(1):7–9. doi:10.1038/jid.2011.359 PubMedGoogle Scholar
  102. Haefeli RH, Erb M, Gemperli AC et al (2011) NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels. PLoS ONE 6(3):e17963. doi:10.1371/journal.pone.0017963 PubMedCentralPubMedGoogle Scholar
  103. Hagen T (2012) Oxygen versus Reactive Oxygen in the Regulation of HIF-1: The Balance Tips. Biochem Res Int 2012:5. doi:10.1155/2012/436981 Google Scholar
  104. Hamilton J, Laurin J (2008) Drug-Induced Cholestasis. In: Lindor K, Talwalkar J (eds) Cholestatic Liver Disease. Humana Press, Clin Gastroenterol, pp 21–43Google Scholar
  105. Hayes MA, Pickering DB (1985) Comparative cytopathology of primary rat hepatocyte cultures exposed to aflatoxin B1, acetaminophen, and other hepatotoxins. Toxicol Appl Pharmacol 80(2):345–356PubMedGoogle Scholar
  106. He J, Lee JH, Febbraio M, Xie W (2011) The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease. Exp Biol Med (Maywood) 236(10):1116–1121. doi:10.1258/ebm.2011.011128 Google Scholar
  107. Hempel JD, Pietruszko R (1981) Selective chemical modification of human liver aldehyde dehydrogenases E1 and E2 by iodoacetamide. J Biol Chem 256(21):10889–10896PubMedGoogle Scholar
  108. Henry TR, Wallace KB (1995) Differential mechanisms of induction of the mitochondrial permeability transition by quinones of varying chemical reactivities. Toxicol Appl Pharmacol 134(2):195–203. doi:10.1006/taap.1995.1184 PubMedGoogle Scholar
  109. Higgins LG, Hayes JD (2011) The cap’n’collar transcription factor Nrf2 mediates both intrinsic resistance to environmental stressors and an adaptive response elicited by chemopreventive agents that determines susceptibility to electrophilic xenobiotics. Chem Biol Interact 192(1–2):37–45. doi:10.1016/j.cbi.2010.09.025 PubMedGoogle Scholar
  110. Hinson JA, Roberts DW, James LP (2010) Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol 196:369–405. doi:10.1007/978-3-642-00663-0_12
  111. Hoehme S, Brulport M, Bauer A et al (2010) Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci USA 107(23):10371–10376. doi:10.1073/pnas.0909374107 PubMedCentralPubMedGoogle Scholar
  112. Hoogendoorn S, Willems L, Florea B, Overkleeft H (2011) Hypersensitive response to over-reactive cysteines. Angew Chem Int Ed Engl 50(24):5434–5436. doi:10.1002/anie.201100938 PubMedGoogle Scholar
  113. Horikawa M, Kato Y, Tyson CA, Sugiyama Y (2003) Potential cholestatic activity of various therapeutic agents assessed by bile canalicular membrane vesicles isolated from rats and humans. Drug Metab Pharmacokinet 18(1):16–22PubMedGoogle Scholar
  114. Hostetler KY, Matsuzawa Y (1981) Studies on the mechanism of drug-induced lipidosis. Cationic amphiphilic drug inhibition of lysosomal phospholipases A and C. Biochem Pharmacol 30(10):1121–1126PubMedGoogle Scholar
  115. Hostetler KY, Reasor MJ, Walker ER, Yazaki PJ, Frazee BW (1986) Role of phospholipase A inhibition in amiodarone pulmonary toxicity in rats. Biochim Biophys Acta 875(2):400–405PubMedGoogle Scholar
  116. Housset C, Rockey DC, Bissell DM (1993) Endothelin receptors in rat liver: lipocytes as a contractile target for endothelin 1. Proc Natl Acad Sci USA 90(20):9266–9270PubMedCentralPubMedGoogle Scholar
  117. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC (2003) Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 23(24):9361–9374PubMedCentralPubMedGoogle Scholar
  118. Hussain MM (2002) Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 44(1):22–32. doi:10.1194/jlr.R200014-JLR200 Google Scholar
  119. Hussain MM, Rava P, Walsh M, Rana M, Iqbal J (2012) Multiple functions of microsomal triglyceride transfer protein. Nutr Metab (Lond) 9:14. doi:10.1186/1743-7075-9-14 Google Scholar
  120. inchem.org In Chem Data Sheet. In. http://www.inchem.org/documents/pims/pharm/rifam.htm#SubSectionTitle:7.2.1. Accessed 17 Jan 2013
  121. Isenberg JS, Klaunig JE (2000) Role of the mitochondrial membrane permeability transition (MPT) in rotenone-induced apoptosis in liver cells. Toxicol Sci 53(2):340–351PubMedGoogle Scholar
  122. Ishihara Y, Shiba D, Shimamoto N (2006) Enhancement of DMNQ-induced hepatocyte toxicity by cytochrome P450 inhibition. Toxicol Appl Pharmacol 214(2):109–117. doi:10.1016/j.taap.2005.12.003 PubMedGoogle Scholar
  123. Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347(6294):645–650. doi:10.1038/347645a0 PubMedGoogle Scholar
  124. Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ (2002) Mechanisms of hepatotoxicity. Toxicol Sci 65(2):166–176PubMedGoogle Scholar
  125. Jennings P (2013) Stress response pathways, toxicity pathways and adverse outcome pathways. Arch Toxicol 87(1):13–14. doi:10.1007/s00204-012-0974-4 PubMedGoogle Scholar
  126. Jennings P, Limonciel A, Felice L, Leonard MO (2013) An overview of transcriptional regulation in response to toxicological insult. Arch Toxicol 87(1):49–72. doi:10.1007/s00204-012-0919-y PubMedGoogle Scholar
  127. Jones HP, Ghai G, Petrone WF, McCord JM (1982) Calmodulin-dependent stimulation of the NADPH oxidase of human neutrophils. Biochim Biophys Acta 714(1):152–156PubMedGoogle Scholar
  128. Jones SA, Moore LB, Shenk JL et al (2000) The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 14(1):27–39. doi:10.1210/mend.14.1.0409 PubMedGoogle Scholar
  129. Jung SA, Chung YH, Park NH et al (2000) Experimental model of hepatic fibrosis following repeated periportal necrosis induced by allylalcohol. Scand J Gastroenterol 35(9):969–975PubMedGoogle Scholar
  130. Juvet LK, Andresen SM, Schuster GU et al (2003) On the role of liver X receptors in lipid accumulation in adipocytes. Mol Endocrinol 17(2):172–182. doi:10.1210/me.2001-0210 PubMedGoogle Scholar
  131. Kaiser JP, Lipscomb JC, Wesselkamper SC (2012) Putative mechanisms of environmental chemical-induced steatosis. Int J Toxicol 31(6):551–563. doi:10.1177/1091581812466418 PubMedGoogle Scholar
  132. Karczewski JM, Peters JG, Noordhoek J (1999a) Prevention of oxidant-induced cell death in Caco-2 colon carcinoma cells after inhibition of poly(ADP-ribose) polymerase and Ca2+ chelation: involvement of a common mechanism. Biochem Pharmacol 57(1):19–26PubMedGoogle Scholar
  133. Karczewski JM, Peters JG, Noordhoek J (1999b) Quinone toxicity in DT-diaphorase-efficient and -deficient colon carcinoma cell lines. Biochem Pharmacol 57(1):27–37PubMedGoogle Scholar
  134. Karki P, Lee J, Shin SY, Cho B, Park IS (2005) Kinetic comparison of procaspase-3 and caspase-3. Arch Biochem Biophys 442(1):125–132. doi:10.1016/j.abb.2005.07.023 PubMedGoogle Scholar
  135. Kennedy JA, Unger SA, Horowitz JD (1996) Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. Biochem Pharmacol 52(2):273–280PubMedGoogle Scholar
  136. Kesterson JW, Granneman GR, Machinist JM (1984) The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies. Hepatology 4(6):1143–1152PubMedGoogle Scholar
  137. Kiang TK, Teng XW, Surendradoss J, Karagiozov S, Abbott FS, Chang TK (2011) Glutathione depletion by valproic acid in sandwich-cultured rat hepatocytes: role of biotransformation and temporal relationship with onset of toxicity. Toxicol Appl Pharmacol 252(3):318–324. doi:10.1016/j.taap.2011.03.004 PubMedGoogle Scholar
  138. Kir S, Zhang Y, Gerard RD, Kliewer SA, Mangelsdorf DJ (2012) Nuclear receptors HNF4alpha and LRH-1 cooperate in regulating Cyp7a1 in vivo. J Biol Chem 287(49):41334–41341. doi:10.1074/jbc.M112.421834 PubMedCentralPubMedGoogle Scholar
  139. Kliewer SA, Forman BM, Blumberg B et al (1994) Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91(15):7355–7359PubMedCentralPubMedGoogle Scholar
  140. Knudsen TB, Houck KA, Sipes NS et al (2011) Activity profiles of 309 ToxCast chemicals evaluated across 292 biochemical targets. Toxicology 282(1–2):1–15. doi:10.1016/j.tox.2010.12.010 PubMedGoogle Scholar
  141. Kodama I, Kamiya K, Toyama J (1999) Amiodarone: ionic and cellular mechanisms of action of the most promising class III agent. Am J Cardiol 84(9A):20R–28RPubMedGoogle Scholar
  142. Kodavanti UP, Mehendale HM (1990) Cationic amphiphilic drugs and phospholipid storage disorder. Pharmacol Rev 42(4):327–354PubMedGoogle Scholar
  143. Kohl R, Zhou J, Brune B (2006) Reactive oxygen species attenuate nitric-oxide-mediated hypoxia-inducible factor-1alpha stabilization. Free Radical Biol Med 40(8):1430–1442. doi:10.1016/j.freeradbiomed.2005.12.012 Google Scholar
  144. Kon K, Kim JS, Jaeschke H, Lemasters JJ (2004) Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology 40(5):1170–1179. doi:10.1002/hep.20437 PubMedGoogle Scholar
  145. Kosters A, Karpen SJ (2008) Bile acid transporters in health and disease. Xenobiotica 38(7–8):1043–1071. doi:10.1080/00498250802040584 PubMedCentralPubMedGoogle Scholar
  146. Kramer OH, Zhu P, Ostendorff HP et al (2003) The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J 22(13):3411–3420. doi:10.1093/emboj/cdg315 PubMedCentralPubMedGoogle Scholar
  147. Kremer JM (2004) Toward a better understanding of methotrexate. Arthritis Rheum 50(5):1370–1382. doi:10.1002/art.20278 PubMedGoogle Scholar
  148. Kroetz DL, Yook P, Costet P, Bianchi P, Pineau T (1998) Peroxisome proliferator-activated receptor alpha controls the hepatic CYP4A induction adaptive response to starvation and diabetes. J Biol Chem 273(47):31581–31589PubMedGoogle Scholar
  149. Kubo M, Hostetler KY (1985) Mechanism of cationic amphiphilic drug inhibition of purified lysosomal phospholipase A1. Biochemistry 24(23):6515–6520PubMedGoogle Scholar
  150. Kumudavalli I, Moreland BH, Watts DC (1970) Properties and reaction with iodoacetamide of adenosine 5′-triphosphate-creatine phosphotransferase from human skeletal muscle. Further evidence about the role of the essential thiol group in relation to the mechanism of action. Biochem J 117(3):513–523PubMedCentralPubMedGoogle Scholar
  151. Labbe G, Pessayre D, Fromenty B (2008) Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol 22(4):335–353. doi:10.1111/j.1472-8206.2008.00608.x PubMedGoogle Scholar
  152. Laffitte BA, Chao LC, Li J et al (2003) Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc Natl Acad Sci USA 100(9):5419–5424. doi:10.1073/pnas.0830671100 PubMedCentralPubMedGoogle Scholar
  153. Larosche I, Letteron P, Fromenty B et al (2007) Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver. J Pharmacol Exp Ther 321(2):526–535. doi:10.1124/jpet.106.114546 PubMedGoogle Scholar
  154. Larrey D, Pageaux GP (1997) Genetic predisposition to drug-induced hepatotoxicity. J Hepatol 26(Suppl 2):12–21PubMedGoogle Scholar
  155. Lash LH, Tokarz JJ, Chen Z, Pedrosi BM, Woods EB (1996) ATP depletion by iodoacetate and cyanide in renal distal tubular cells. J Pharmacol Exp Ther 276(1):194–205PubMedGoogle Scholar
  156. Lee YS, Kang YS, Lee SH, Kim JA (2000) Role of NAD(P)H oxidase in the tamoxifen-induced generation of reactive oxygen species and apoptosis in HepG2 human hepatoblastoma cells. Cell Death Differ 7(10):925–932. doi:10.1038/sj.cdd.4400717 PubMedGoogle Scholar
  157. Lee MH, Hong I, Kim M et al (2007) Gene expression profiles of murine fatty liver induced by the administration of valproic acid. Toxicol Appl Pharmacol 220(1):45–59. doi:10.1016/j.taap.2006.12.016 PubMedGoogle Scholar
  158. Lee JH, Wada T, Febbraio M et al (2010) A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. Gastroenterology 139(2):653–663. doi:10.1053/j.gastro.2010.03.033 PubMedCentralPubMedGoogle Scholar
  159. Lefebvre P, Chinetti G, Fruchart JC, Staels B (2006) Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 116(3):571–580. doi:10.1172/JCI27989 PubMedCentralPubMedGoogle Scholar
  160. Lelliott CJ, Lopez M, Curtis RK et al (2005) Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis. FASEB J 19(9):1108–1119. doi:10.1096/fj.04-3196com PubMedGoogle Scholar
  161. Lemasters JJ, Nieminen AL, Qian T, Trost LC, Herman B (1997) The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury. Mol Cell Biochem 174(1–2):159–165PubMedGoogle Scholar
  162. Leonard MO, Limonciel A, Jennings P (2014) Stress response pathways in vitro toxicology systems. Springer, New York, pp 433–458Google Scholar
  163. Letteron P, Sutton A, Mansouri A, Fromenty B, Pessayre D (2003) Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology 38(1):133–140. doi:10.1053/jhep.2003.50309 PubMedGoogle Scholar
  164. Leverve X, Sibille B, Devin A, Piquet MA, Espie P, Rigoulet M (1998) Oxidative phosphorylation in intact hepatocytes: quantitative characterization of the mechanisms of change in efficiency and cellular consequences. Mol Cell Biochem 184(1–2):53–65PubMedGoogle Scholar
  165. Li T, Chiang JY (2005) Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription. Am J Physiol Gastrointest Liver Physiol 288(1):G74–G84. doi:10.1152/ajpgi.00258.2004 PubMedGoogle Scholar
  166. Li J, Bronk BS, Dirlam JP et al (2007) In vitro and in vivo profile of 5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), a novel potent MTP inhibitor for obesity. Bioorg Med Chem Lett 17(7):1996–1999. doi:10.1016/j.bmcl.2007.01.018 PubMedGoogle Scholar
  167. Limonciel A, Aschauer L, Wilmes A et al (2011) Lactate is an ideal non-invasive marker for evaluating temporal alterations in cell stress and toxicity in repeat dose testing regimes. Toxicol In Vitro Int J Publ Assoc BIBRA 25(8):1855–1862. doi:10.1016/j.tiv.2011.05.018 Google Scholar
  168. Limonciel A, Wilmes A, Aschauer L et al (2012) Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells. Arch Toxicol 86(11):1741–1751. doi:10.1007/s00204-012-0897-0 PubMedGoogle Scholar
  169. Lindsay K, Fraser AD, Layton A, Goodfield M, Gruss H, Gough A (2009) Liver fibrosis in patients with psoriasis and psoriatic arthritis on long-term, high cumulative dose methotrexate therapy. Rheumatology (Oxford) 48(5):569–572. doi:10.1093/rheumatology/kep023 Google Scholar
  170. Liu H, Lightfoot R, Stevens JL (1996) Activation of heat shock factor by alkylating agents is triggered by glutathione depletion and oxidation of protein thiols. J Biol Chem 271(9):4805–4812PubMedGoogle Scholar
  171. Liu J, Wu KC, Lu YF, Ekuase E, Klaassen CD (2013) Nrf2 protection against liver injury produced by various hepatotoxicants. Oxid Med Cell Longev 2013:305861. doi:10.1155/2013/305861 PubMedCentralPubMedGoogle Scholar
  172. LoPachin RM, Barber DS, Gavin T (2008) Molecular mechanisms of the conjugated alpha, beta-unsaturated carbonyl derivatives: relevance to neurotoxicity and neurodegenerative diseases. Toxicol Sci Off J Soc Toxicol 104(2):235–249. doi:10.1093/toxsci/kfm301 Google Scholar
  173. Lowe R, Mussa HY, Nigsch F, Glen RC, Mitchell JB (2012) Predicting the mechanism of phospholipidosis. J Cheminform 4:2. doi:10.1186/1758-2946-4-2 PubMedCentralPubMedGoogle Scholar
  174. Luder AS, Parks JK, Frerman F, Parker WD Jr (1990) Inactivation of beef brain alpha-ketoglutarate dehydrogenase complex by valproic acid and valproic acid metabolites. Possible mechanism of anticonvulsant and toxic actions. J Clin Invest 86(5):1574–1581. doi:10.1172/JCI114877 PubMedCentralPubMedGoogle Scholar
  175. Luis PB, Ruiter JP, Aires CC et al (2007) Valproic acid metabolites inhibit dihydrolipoyl dehydrogenase activity leading to impaired 2-oxoglutarate-driven oxidative phosphorylation. Biochim Biophys Acta 1767(9):1126–1133. doi:10.1016/j.bbabio.2007.06.007 PubMedGoogle Scholar
  176. Lund EG, Peterson LB, Adams AD et al (2006) Different roles of liver X receptor alpha and beta in lipid metabolism: effects of an alpha-selective and a dual agonist in mice deficient in each subtype. Biochem Pharmacol 71(4):453–463. doi:10.1016/j.bcp.2005.11.004 PubMedGoogle Scholar
  177. Ma X, Idle JR, Gonzalez FJ (2008) The pregnane X receptor: from bench to bedside. Expert Opin Drug Metab Toxicol 4(7):895–908. doi:10.1517/17425255.4.7.895 PubMedCentralPubMedGoogle Scholar
  178. Ma Y, Huang Y, Yan L, Gao M, Liu D (2013) Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res 30(5):1447–1457. doi:10.1007/s11095-013-0986-7 PubMedCentralPubMedGoogle Scholar
  179. Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA (2002) Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62(3):638–646PubMedGoogle Scholar
  180. Mailloux RJ, Appanna VD (2007) Aluminum toxicity triggers the nuclear translocation of HIF-1alpha and promotes anaerobiosis in hepatocytes. Toxicol In Vitro Int J Publ Assoc BIBRA 21(1):16–24. doi:10.1016/j.tiv.2006.07.013 Google Scholar
  181. Manibusan MK, Odin M, Eastmond DA (2007) Postulated carbon tetrachloride mode of action: a review. J Environ Sci Health Part C Environ Carcinog Ecotoxicol Rev 25(3):185–209. doi:10.1080/10590500701569398 Google Scholar
  182. Marion TL, Perry CH, St Claire RL, Brouwer KL III (2012) Endogenous bile acid disposition in rat and human sandwich-cultured hepatocytes. Toxicol Appl Pharmacol 261(1):1–9. doi:10.1016/j.taap.2012.02.002 PubMedCentralPubMedGoogle Scholar
  183. Martin WJ 2nd, Kachel DL, Vilen T, Natarajan V (1989) Mechanism of phospholipidosis in amiodarone pulmonary toxicity. J Pharmacol Exp Ther 251(1):272–278PubMedGoogle Scholar
  184. Martin MT, Dix DJ, Judson RS et al (2010) Impact of environmental chemicals on key transcription regulators and correlation to toxicity end points within EPA’s ToxCast program. Chem Res Toxicol 23(3):578–590. doi:10.1021/tx900325g PubMedGoogle Scholar
  185. Martyniuk CJ, Fang B, Koomen JM et al (2011) Molecular mechanism of glyceraldehyde-3-phosphate dehydrogenase inactivation by alpha, beta-unsaturated carbonyl derivatives. Chem Res Toxicol 24(12):2302–2311. doi:10.1021/tx200437y PubMedCentralPubMedGoogle Scholar
  186. Maruoka N, Murata T, Omata N et al (2007) Effects of chlorpromazine on plasma membrane permeability and fluidity in the rat brain: a dynamic positron autoradiography and fluorescence polarization study. Prog Neuropsychopharmacol Biol Psychiatry 31(1):178–186. doi:10.1016/j.pnpbp.2006.08.019 PubMedGoogle Scholar
  187. Matthews J, Gustafsson JA (2006) Estrogen receptor and aryl hydrocarbon receptor signaling pathways. Nucl Recept Signal 4:e016. doi:10.1621/nrs.04016 PubMedCentralPubMedGoogle Scholar
  188. Matthews RG, Ballou DP, Thorpe C, Williams CH Jr (1977) Ion pair formation in pig heart lipoamide dehydrogenase: rationalization of pH profiles for reactivity of oxidized enzyme with dihydrolipoamide and 2-electron-reduced enzyme with lipoamide and iodoacetamide. J Biol Chem 252(10):3199–3207PubMedGoogle Scholar
  189. Mayerson AB, Hundal RS, Dufour S et al (2002) The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51(3):797–802PubMedCentralPubMedGoogle Scholar
  190. Mehendale HM (2005) Tissue repair: an important determinant of final outcome of toxicant-induced injury. Toxicol Pathol 33(1):41–51. doi:10.1080/01926230590881808 PubMedGoogle Scholar
  191. Miao B, Zondlo S, Gibbs S et al (2004) Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator. J Lipid Res 45(8):1410–1417. doi:10.1194/jlr.M300450-JLR200 PubMedGoogle Scholar
  192. Miao W, Hu L, Scrivens PJ, Batist G (2005) Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes. J Biol Chem 280(21):20340–20348. doi:10.1074/jbc.M412081200 PubMedGoogle Scholar
  193. Mitro N, Vargas L, Romeo R, Koder A, Saez E (2007) T0901317 is a potent PXR ligand: implications for the biology ascribed to LXR. FEBS Lett 581(9):1721–1726. doi:10.1016/j.febslet.2007.03.047 PubMedGoogle Scholar
  194. Mohi-ud-din R, Lewis JH (2004) Drug- and chemical-induced cholestasis. Clin Liver Dis 8(1):95–132. doi:10.1016/s1089-3261(03)00124-7 PubMedGoogle Scholar
  195. Monti B, Polazzi E, Contestabile A (2009) Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection. Curr Mol Pharmacol 2(1):95–109PubMedGoogle Scholar
  196. Moradpour D, Altorfer J, Flury R et al (1994) Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis. Hepatology 20(6):1437–1441PubMedGoogle Scholar
  197. Morgan WA (1995) Pyridine nucleotide hydrolysis and interconversion in rat hepatocytes during oxidative stress. Biochem Pharmacol 49(9):1179–1184PubMedGoogle Scholar
  198. Morgan RE, Trauner M, van Staden CJ et al (2010) Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci 118(2):485–500. doi:10.1093/toxsci/kfq269 PubMedGoogle Scholar
  199. Motojima K (1998) Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J Biol Chem 273(27):16710–16714. doi:10.1074/jbc.273.27.16710 PubMedGoogle Scholar
  200. Mottino AD, Catania VA (2008) Hepatic drug transporters and nuclear receptors: regulation by therapeutic agents. World J Gastroenterol 14(46):7068–7074PubMedCentralPubMedGoogle Scholar
  201. Moya M, Gomez-Lechon MJ, Castell JV, Jover R (2010) Enhanced steatosis by nuclear receptor ligands: a study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile. Chem Biol Interact 184(3):376–387. doi:10.1016/j.cbi.2010.01.008 PubMedGoogle Scholar
  202. Murray IA, Flaveny CA, Chiaro CR et al (2011) Suppression of cytokine-mediated complement factor gene expression through selective activation of the Ah receptor with 3′,4′-dimethoxy-alpha-naphthoflavone. Mol Pharmacol 79(3):508–519. doi:10.1124/mol.110.069369 PubMedCentralPubMedGoogle Scholar
  203. Nadanaciva S, Bernal A, Aggeler R, Capaldi R, Will Y (2007) Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays. Toxicol In Vitro Int J Publ Assoc BIBRA 21(5):902–911. doi:10.1016/j.tiv.2007.01.011 Google Scholar
  204. Narayanan GA, Murray IA, Krishnegowda G, Amin S, Perdew GH (2012) Selective aryl hydrocarbon receptor modulator-mediated repression of CD55 expression induced by cytokine exposure. J Pharmacol Exp Ther 342(2):345–355. doi:10.1124/jpet.112.193482 PubMedCentralPubMedGoogle Scholar
  205. Nault R, Forgacs AL, Dere E, Zacharewski TR (2013) Comparisons of differential gene expression elicited by TCDD, PCB126, betaNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver. Toxicol Lett 223(1):52–59. doi:10.1016/j.toxlet.2013.08.013 PubMedCentralPubMedGoogle Scholar
  206. Neptune M, McCreery RL (1978) Chemical and electrochemical oxidation of 7-hydroxychlorpromazine. J Med Chem 21(4):362–368PubMedGoogle Scholar
  207. Nguyen LP, Bradfield CA (2008) The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 21(1):102–116. doi:10.1021/tx7001965 PubMedCentralPubMedGoogle Scholar
  208. Nguyen MC, Stewart RB, Banerji MA, Gordon DH, Kral JG (2001) Relationships between tamoxifen use, liver fat and body fat distribution in women with breast cancer. Int J Obes Relat Metab Disord 25(2):296–298. doi:10.1038/sj.ijo.0801488 PubMedGoogle Scholar
  209. Nieminen AL, Saylor AK, Herman B, Lemasters JJ (1994) ATP depletion rather than mitochondrial depolarization mediates hepatocyte killing after metabolic inhibition. Am J Physiol 267(1 Pt 1):C67–C74PubMedGoogle Scholar
  210. Niknahad H, Siraki AG, Shuhendler A et al (2003) Modulating carbonyl cytotoxicity in intact rat hepatocytes by inhibiting carbonyl-metabolizing enzymes. I. Aliphatic alkenals. Chem Biol Interactions 143–144:107–117Google Scholar
  211. Nioi P, Perry BK, Wang EJ, Gu YZ, Snyder RD (2007) In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies. Toxicol Sci 99(1):162–173. doi:10.1093/toxsci/kfm157 PubMedGoogle Scholar
  212. Niranjan BG, Bhat NK, Avadhani NG (1982) Preferential attack of mitochondrial DNA by aflatoxin B1 during hepatocarcinogenesis. Science 215(4528):73–75PubMedGoogle Scholar
  213. Nishino M, Hayakawa K, Nakamura Y, Morimoto T, Mukaihara S (2003) Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR Am J Roentgenol 180(1):129–134. doi:10.2214/ajr.180.1.1800129 PubMedGoogle Scholar
  214. Nishizawa H, Yamagata K, Shimomura I et al (2002) Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation. J Biol Chem 277(2):1586–1592. doi:10.1074/jbc.M104301200 PubMedGoogle Scholar
  215. Nolte RT, Wisely GB, Westin S et al (1998) Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395(6698):137–143. doi:10.1038/25931 PubMedGoogle Scholar
  216. Noordeen NA, Khera TK, Sun G et al (2010) Carbohydrate-responsive element-binding protein (ChREBP) is a negative regulator of ARNT/HIF-1beta gene expression in pancreatic islet beta-cells. Diabetes 59(1):153–160. doi:10.2337/db08-0868 PubMedCentralPubMedGoogle Scholar
  217. Obidoa O, Obonna EE (1981) Aflatoxin inhibition of reversed electron transfer in rat liver mitochondria in vitro. Biochem Med 26(1):1–7PubMedGoogle Scholar
  218. O’Brien T, Babcock G, Cornelius J et al (2000) A comparison of apoptosis and necrosis induced by hepatotoxins in HepG2 cells. Toxicol Appl Pharmacol 164(3):280–290. doi:10.1006/taap.2000.8917 PubMedGoogle Scholar
  219. Ogawa Y, Murata Y, Nishioka A, Inomata T, Yoshida S (1998) Tamoxifen-induced fatty liver in patients with breast cancer. Lancet 351(9104):725. doi:10.1016/s0140-6736(05)78493-2 PubMedGoogle Scholar
  220. Ohno Y, Ormstad K, Ross D, Orrenius S (1985) Mechanism of allyl alcohol toxicity and protective effects of low-molecular-weight thiols studied with isolated rat hepatocytes. Toxicol Appl Pharmacol 78(2):169–179PubMedGoogle Scholar
  221. Oien KA, Moffat D, Curry GW et al (1999) Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet 353(9146):36–37. doi:10.1016/s0140-6736(05)74872-8 PubMedGoogle Scholar
  222. Oosterveer MH, Grefhorst A, Groen AK, Kuipers F (2010) The liver X receptor: control of cellular lipid homeostasis and beyond Implications for drug design. Prog Lipid Res 49(4):343–352. doi:10.1016/j.plipres.2010.03.002 PubMedGoogle Scholar
  223. Ory DS (2004) Nuclear receptor signaling in the control of cholesterol homeostasis: have the orphans found a home? Circ Res 95(7):660–670. doi:10.1161/01.RES.0000143422.83209.be PubMedGoogle Scholar
  224. Ostapowicz G, Fontana RJ, Schiodt FV et al (2002) Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 137(12):947–954PubMedGoogle Scholar
  225. Out C, Hageman J, Bloks VW et al (2011) Liver receptor homolog-1 is critical for adequate up-regulation of Cyp7a1 gene transcription and bile salt synthesis during bile salt sequestration. Hepatology 53(6):2075–2085. doi:10.1002/hep.24286 PubMedGoogle Scholar
  226. Ozcan A, Sahin Y (2011) A novel approach for the determination of paracetamol based on the reduction of N-acetyl-p-benzoquinoneimine formed on the electrochemically treated pencil graphite electrode. Anal Chim Acta 685(1):9–14. doi:10.1016/j.aca.2010.11.004 PubMedGoogle Scholar
  227. Pan X, Hussain FN, Iqbal J, Feuerman MH, Hussain MM (2007) Inhibiting proteasomal degradation of microsomal triglyceride transfer protein prevents CCl4-induced steatosis. J Biol Chem 282(23):17078–17089. doi:10.1074/jbc.M701742200 PubMedGoogle Scholar
  228. Park WH, Han YW, Kim SH, Kim SZ (2007) An ROS generator, antimycin A, inhibits the growth of HeLa cells via apoptosis. J Cell Biochem 102(1):98–109. doi:10.1002/jcb.21280 PubMedGoogle Scholar
  229. Parry JD, Pointon AV, Lutz U et al (2009) Pivotal role for two electron reduction in 2,3-dimethoxy-1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone metabolism and kinetics in vivo that prevents liver redox stress. Chem Res Toxicol 22(4):717–725. doi:10.1021/tx800472z PubMedGoogle Scholar
  230. Patel RD, Hollingshead BD, Omiecinski CJ, Perdew GH (2007) Aryl-hydrocarbon receptor activation regulates constitutive androstane receptor levels in murine and human liver. Hepatology 46(1):209–218. doi:10.1002/hep.21671 PubMedCentralPubMedGoogle Scholar
  231. Peraza MA, Burdick AD, Marin HE, Gonzalez FJ, Peters JM (2006) The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR). Toxicol Sci 90(2):269–295. doi:10.1093/toxsci/kfj062 PubMedGoogle Scholar
  232. Peroutka SJ, Synder SH (1980) Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency. Am J Psychiatry 137(12):1518–1522PubMedGoogle Scholar
  233. Peters TS (2005) Do preclinical testing strategies help predict human hepatotoxic potentials? Toxicol Pathol 33(1):146–154. doi:10.1080/01926230590522121 PubMedGoogle Scholar
  234. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276(39):36734–36741. doi:10.1074/jbc.M101287200 PubMedGoogle Scholar
  235. Pogribny IP, Tryndyak VP, Bagnyukova TV et al (2009) Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet. J Hepatol 51(1):176–186. doi:10.1016/j.jhep.2009.03.021 PubMedCentralPubMedGoogle Scholar
  236. Pointon AV, Walker TM, Phillips KM et al (2010) Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation. PLoS ONE 5(9):e12733. doi:10.1371/journal.pone.0012733 PubMedCentralPubMedGoogle Scholar
  237. Ponchaut S, van Hoof F, Veitch K (1992) In vitro effects of valproate and valproate metabolites on mitochondrial oxidations. Relevance of CoA sequestration to the observed inhibitions. Biochem Pharmacol 43(11):2435–2442PubMedGoogle Scholar
  238. Prasada Rao KS, Rao SB, Camus PH, Mehendale HM (1986) Effect of amiodarone on Na+-, K+-ATPase and Mg2+-ATPase activities in rat brain synaptosomes. Cell Biochem Funct 4(2):143–151. doi:10.1002/cbf.290040210 PubMedGoogle Scholar
  239. Rafeiro E, Barr SG, Harrison JJ, Racz WJ (1994) Effects of N-acetylcysteine and dithiothreitol on glutathione and protein thiol replenishment during acetaminophen-induced toxicity in isolated mouse hepatocytes. Toxicology 93(2–3):209–224PubMedGoogle Scholar
  240. Raney KD, Meyer DJ, Ketterer B, Harris TM, Guengerich FP (1992) Glutathione conjugation of aflatoxin B1 exo- and endo-epoxides by rat and human glutathione S-transferases. Chem Res Toxicol 5(4):470–478PubMedGoogle Scholar
  241. Rao MS, Reddy JK (2004) PPARalpha in the pathogenesis of fatty liver disease. Hepatology 40(4):783–786. doi:10.1002/hep.20453 PubMedGoogle Scholar
  242. Redegeld FA, Moison RM, Koster AS, Noordhoek J (1992) Depletion of ATP but not of GSH affects viability of rat hepatocytes. Eur J Pharmacol 228(4):229–236PubMedGoogle Scholar
  243. Reid AB, Kurten RC, McCullough SS, Brock RW, Hinson JA (2005) Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes. The Journal of pharmacology and experimental therapeutics 312(2):509–516. doi:10.1124/jpet.104.075945 PubMedGoogle Scholar
  244. Repa JJ, Liang G, Ou J et al (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors. LXRalpha and LXRbeta. Genes Dev 14(22):2819–2830Google Scholar
  245. Reschly EJ, Krasowski MD (2006) Evolution and function of the NR1I nuclear hormone receptor subfamily (VDR, PXR, and CAR) with respect to metabolism of xenobiotics and endogenous compounds. Curr Drug Metab 7(4):349–365PubMedCentralPubMedGoogle Scholar
  246. Rezen T, Rozman D, Pascussi JM, Monostory K (2011) Interplay between cholesterol and drug metabolism. Biochim Biophys Acta 1814(1):146–160. doi:10.1016/j.bbapap.2010.05.014 PubMedGoogle Scholar
  247. Richard S, Guerret S, Gerard F, Tebib JG, Vignon E (2000) Hepatic fibrosis in rheumatoid arthritis patients treated with methotrexate: application of a new semi-quantitative scoring system. Rheumatology (Oxford) 39(1):50–54Google Scholar
  248. Rikans LE, Cai Y (1994) Dithiothreitol reversal of allyl alcohol cytotoxicity in isolated rat hepatocytes. Toxicology 86(1–2):147–161PubMedGoogle Scholar
  249. Rikans LE, Cai Y, Hornbrook KR (1995) Allyl alcohol cytotoxicity in isolated rat hepatocytes: effects of azide, fasting, and fructose. J Toxicol Environ Health 44(1):1–11. doi:10.1080/15287399509531939 PubMedGoogle Scholar
  250. Rikans LE, Cai DY, Hornbrook KR (1996) Oxidation of pyridine nucleotides is an early event in the lethality of allyl alcohol. Toxicology 106(1–3):85–92PubMedGoogle Scholar
  251. Robinson RP, Bartlett JA, Bertinato P et al (2011) Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide. Bioorg Med Chem Lett 21(14):4150–4154. doi:10.1016/j.bmcl.2011.05.099 PubMedGoogle Scholar
  252. Rogue A, Spire C, Brun M, Claude N, Guillouzo A (2010) Gene expression changes induced by PPAR gamma agonists in animal and human liver. PPAR Res 2010:325183. doi:10.1155/2010/325183 PubMedCentralPubMedGoogle Scholar
  253. Roitelman J, Shechter I (1989) Studies on the catalytic site of rat liver HMG-CoA reductase: interaction with CoA-thioesters and inactivation by iodoacetamide. J Lipid Res 30(1):97–107PubMedGoogle Scholar
  254. Rosenberg G (2007) The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci 64(16):2090–2103. doi:10.1007/s00018-007-7079-x PubMedGoogle Scholar
  255. Safe SH (1995) Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. Pharmacol Ther 67(2):247–281PubMedGoogle Scholar
  256. Sajan MP, Satav JG, Bhattacharya RK (1996) Alteration of energy-linked functions in rat hepatic mitochondria following aflatoxin B1 administration. J Biochem Toxicol 11(5):235–241. doi:10.1002/(SICI)1522-7146(1996)11:5<235:AID-JBT4>3.0.CO;2-L PubMedGoogle Scholar
  257. Sakamoto J, Kimura H, Moriyama S et al (2000) Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun 278(3):704–711. doi:10.1006/bbrc.2000.3868 PubMedGoogle Scholar
  258. Salnikow K, An WG, Melillo G, Blagosklonny MV, Costa M (1999) Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors. Carcinogenesis 20(9):1819–1823PubMedGoogle Scholar
  259. Sandau K, Pfeilschifter J, Brune B (1998) Nitrosative and oxidative stress induced heme oxygenase-1 accumulation in rat mesangial cells. Eur J Pharmacol 342(1):77–84PubMedGoogle Scholar
  260. Saphner T, Triest-Robertson S, Li H, Holzman P (2009) The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer. Cancer 115(14):3189–3195. doi:10.1002/cncr.24374 PubMedGoogle Scholar
  261. Sato O, Kuriki C, Fukui Y, Motojima K (2002) Dual promoter structure of mouse and human fatty acid translocase/CD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor alpha and gamma ligands. J Biol Chem 277(18):15703–15711. doi:10.1074/jbc.M110158200 PubMedGoogle Scholar
  262. Sato O, Takanashi N, Motojima K (2007) Third promoter and differential regulation of mouse and human fatty acid translocase/CD36 genes. Mol Cell Biochem 299(1–2):37–43. doi:10.1007/s11010-005-9035-0 PubMedGoogle Scholar
  263. Sawada H, Takami K, Asahi S (2005) A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci 83(2):282–292. doi:10.1093/toxsci/kfh264 PubMedGoogle Scholar
  264. Schachter D (1984) Fluidity and function of hepatocyte plasma membranes. Hepatology 4(1):140–151PubMedGoogle Scholar
  265. Schacke H, Schottelius A, Docke WD et al (2004) Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects. Proc Natl Acad Sci USA 101(1):227–232. doi:10.1073/pnas.0300372101 PubMedCentralPubMedGoogle Scholar
  266. Schadinger SE, Bucher NL, Schreiber BM, Farmer SR (2005) PPARgamma2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes. Am J Physiol Endocrinol Metab 288(6):E1195–E1205. doi:10.1152/ajpendo.00513.2004 PubMedGoogle Scholar
  267. Schmidt MM, Dringen R (2009) Differential effects of iodoacetamide and iodoacetate on glycolysis and glutathione metabolism of cultured astrocytes. Front Neuroenergetics 1:1. doi:10.3389/neuro.14.001.2009 PubMedCentralPubMedGoogle Scholar
  268. Schodel J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR (2011) High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood 117(23):e207–e217. doi:10.1182/blood-2010-10-314427 PubMedCentralPubMedGoogle Scholar
  269. Schoonen WG, Westerink WM, de Roos JA, Debiton E (2005) Cytotoxic effects of 100 reference compounds on Hep G2 and HeLa cells and of 60 compounds on ECC-1 and CHO cells. I mechanistic assays on ROS, glutathione depletion and calcein uptake. Toxicol In Vitro Int J Publ Assoc BIBRA 19(4):505–516. doi:10.1016/j.tiv.2005.01.003 Google Scholar
  270. Schultz JR, Tu H, Luk A et al (2000) Role of LXRs in control of lipogenesis. Genes Dev 14(22):2831–2838PubMedCentralPubMedGoogle Scholar
  271. Schwarz M, Gocht T (2011) Towards the replacement of in vivo repeated dose systemic toxicity testing, vol 1. (self-publishing), Paris, FranceGoogle Scholar
  272. Seeman P (1977) Anti-schizophrenic drugs–membrane receptor sites of action. Biochem Pharmacol 26(19):1741–1748PubMedGoogle Scholar
  273. Semenza GL (2001) HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 13(2):167–171PubMedGoogle Scholar
  274. Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12(12):5447–5454PubMedCentralPubMedGoogle Scholar
  275. Shaikh NA, Downar E, Butany J (1987) Amiodarone—an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine. Mol Cell Biochem 76(2):163–172PubMedGoogle Scholar
  276. Shen C, Cheng X, Li D, Meng Q (2009) Investigation of rifampicin-induced hepatotoxicity in rat hepatocytes maintained in gel entrapment culture. Cell Biol Toxicol 25(3):265–274. doi:10.1007/s10565-008-9076-8 PubMedGoogle Scholar
  277. Sherer TB, Richardson JR, Testa CM et al (2007) Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson’s disease. J Neurochem 100(6):1469–1479. doi:10.1111/j.1471-4159.2006.04333.x PubMedGoogle Scholar
  278. Signorelli S, Jennings P, Leonard MO, Pfaller W (2010) Differential effects of hypoxic stress in alveolar epithelial cells and microvascular endothelial cells. Cell Physiol Biochem 25(1):135–144. doi:10.1159/000272066 PubMedGoogle Scholar
  279. Silva MF, Aires CC, Luis PB et al (2008) Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inherit Metab Dis 31(2):205–216. doi:10.1007/s10545-008-0841-x PubMedGoogle Scholar
  280. Simeonova PP, Gallucci RM, Hulderman T et al (2001) The role of tumor necrosis factor-alpha in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride. Toxicol Appl Pharmacol 177(2):112–120. doi:10.1006/taap.2001.9304 PubMedGoogle Scholar
  281. Smith KJ, Murray IA, Tanos R et al (2011) Identification of a high-affinity ligand that exhibits complete aryl hydrocarbon receptor antagonism. J Pharmacol Exp Ther 338(1):318–327. doi:10.1124/jpet.110.178392 PubMedCentralPubMedGoogle Scholar
  282. Song Y, Buettner GR (2010) Thermodynamic and kinetic considerations for the reaction of semiquinone radicals to form superoxide and hydrogen peroxide. Free Radical Biol Med 49(6):919–962. doi:10.1016/j.freeradbiomed.2010.05.009 Google Scholar
  283. Soshilov A, Denison MS (2008) Role of the Per/Arnt/Sim domains in ligand-dependent transformation of the aryl hydrocarbon receptor. J Biol Chem 283(47):32995–33005. doi:10.1074/jbc.M802414200 PubMedCentralPubMedGoogle Scholar
  284. Sparkenbaugh EM, Saini Y, Greenwood KK et al (2011) The role of hypoxia-inducible factor-1alpha in acetaminophen hepatotoxicity. J Pharmacol Exp Ther 338(2):492–502. doi:10.1124/jpet.111.180521 PubMedCentralPubMedGoogle Scholar
  285. Spycher S, Smejtek P, Netzeva TI, Escher BI (2008) Toward a class-independent quantitative structure–activity relationship model for uncouplers of oxidative phosphorylation. Chem Res Toxicol 21(4):911–927. doi:10.1021/tx700391f PubMedGoogle Scholar
  286. Stamper BD, Mohar I, Kavanagh TJ, Nelson SD (2011) Proteomic analysis of acetaminophen-induced changes in mitochondrial protein expression using spectral counting. Chem Res Toxicol 24(4):549–558. doi:10.1021/tx1004198 PubMedCentralPubMedGoogle Scholar
  287. Stejskalova L, Rulcova A, Vrzal R, Dvorak Z, Pavek P (2013) Dexamethasone accelerates degradation of aryl hydrocarbon receptor (AHR) and suppresses CYP1A1 induction in placental JEG-3 cell line. Toxicol Lett 223(2):183–191. doi:10.1016/j.toxlet.2013.09.014 PubMedGoogle Scholar
  288. Stevens JL, Liu H, Halleck M, Bowes RC, Chen QM, van de Water B (2000) Linking gene expression to mechanisms of toxicity. Toxicol Lett 112–113:479–486Google Scholar
  289. Tacka KA, Dabrowiak JC, Goodisman J, Souid AK (2002) Kinetic analysis of the reactions of 4-hydroperoxycyclophosphamide and acrolein with glutathione, mesna, and WR-1065. Drug Metab Dispos 30(8):875–882PubMedGoogle Scholar
  290. Takahashi E (2008) Anoxic cell core can promote necrotic cell death in cardiomyocytes at physiological extracellular PO2. Am J Physiol Heart Circ Physiol 294(6):H2507–H2515. doi:10.1152/ajpheart.00168.2008 PubMedGoogle Scholar
  291. Tan AS, Berridge MV (2010) Evidence for NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated quinone-dependent redox cycling via plasma membrane electron transport: a sensitive cellular assay for NQO1. Free Radical Biol Med 48(3):421–429. doi:10.1016/j.freeradbiomed.2009.11.016 Google Scholar
  292. Tang W (2007) Drug metabolite profiling and elucidation of drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 3(3):407–420. doi:10.1517/17425255.3.3.407 PubMedGoogle Scholar
  293. Tanos R, Murray IA, Smith PB, Patterson A, Perdew GH (2012a) Role of the Ah receptor in homeostatic control of fatty acid synthesis in the liver. Toxicol Sci 129(2):372–379. doi:10.1093/toxsci/kfs204 PubMedCentralPubMedGoogle Scholar
  294. Tanos R, Patel RD, Murray IA, Smith PB, Patterson AD, Perdew GH (2012b) Aryl hydrocarbon receptor regulates the cholesterol biosynthetic pathway in a dioxin response element-independent manner. Hepatology 55(6):1994–2004. doi:10.1002/hep.25571 PubMedCentralPubMedGoogle Scholar
  295. Tee LB, Boobis AR, Huggett AC, Davies DS (1986) Reversal of acetaminophen toxicity in isolated hamster hepatocytes by dithiothreitol. Toxicol Appl Pharmacol 83(2):294–314PubMedGoogle Scholar
  296. Thieme TM, Steri R, Proschak E, Paulke A, Schneider G, Schubert-Zsilavecz M (2010) Rational design of a pirinixic acid derivative that acts as subtype-selective PPARgamma modulator. Bioorg Med Chem Lett 20(8):2469–2473. doi:10.1016/j.bmcl.2010.03.008 PubMedGoogle Scholar
  297. Thomas R, Kim MH (2007) Targeting the hypoxia inducible factor pathway with mitochondrial uncouplers. Mol Cell Biochem 296(1–2):35–44. doi:10.1007/s11010-006-9295-3 PubMedGoogle Scholar
  298. Thomas D, Gut B, Wendt-Nordahl G, Kiehn J (2002) The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. J Pharmacol Exp Ther 300(2):543–548PubMedGoogle Scholar
  299. Thomas D, Wu K, Kathofer S et al (2003) The antipsychotic drug chlorpromazine inhibits HERG potassium channels. Br J Pharmacol 139(3):567–574. doi:10.1038/sj.bjp.0705283 PubMedCentralPubMedGoogle Scholar
  300. Tien ES, Negishi M (2006) Nuclear receptors CAR and PXR in the regulation of hepatic metabolism. Xenobiotica 36(10–11):1152–1163. doi:10.1080/00498250600861827 PubMedCentralPubMedGoogle Scholar
  301. Tirona RG, Lee W, Leake BF et al (2003) The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med 9(2):220–224. doi:10.1038/nm815 PubMedGoogle Scholar
  302. Tirumalai R, Rajesh Kumar T, Mai KH, Biswal S (2002) Acrolein causes transcriptional induction of phase II genes by activation of Nrf2 in human lung type II epithelial (A549) cells. Toxicol Lett 132(1):27–36PubMedGoogle Scholar
  303. Toxbank In. http://wiki.toxbank.net/wiki/. Accessed 22 Oct 2013
  304. Toxopeus C, van Holsteijn I, Thuring JW, Blaauboer BJ, Noordhoek J (1993) Cytotoxicity of menadione and related quinones in freshly isolated rat hepatocytes: effects on thiol homeostasis and energy charge. Arch Toxicol 67(10):674–679PubMedGoogle Scholar
  305. Tryndyak VP, Muskhelishvili L, Kovalchuk O et al (2006) Effect of long-term tamoxifen exposure on genotoxic and epigenetic changes in rat liver: implications for tamoxifen-induced hepatocarcinogenesis. Carcinogenesis 27(8):1713–1720. doi:10.1093/carcin/bgl050 PubMedGoogle Scholar
  306. Tryndyak VP, Kovalchuk O, Muskhelishvili L et al (2007) Epigenetic reprogramming of liver cells in tamoxifen-induced rat hepatocarcinogenesis. Mol Carcinog 46(3):187–197. doi:10.1002/mc.20263 PubMedGoogle Scholar
  307. Uyeda K, Repa JJ (2006) Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab 4(2):107–110. doi:10.1016/j.cmet.2006.06.008 PubMedGoogle Scholar
  308. Van Dyke RW, Scharschmidt BF (1987) Effects of chlorpromazine on Na+-K+-ATPase pumping and solute transport in rat hepatocytes. Am J Physiol 253(5 Pt 1):G613–G621PubMedGoogle Scholar
  309. Varga T, Czimmerer Z, Nagy L (2011) PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta 1812(8):1007–1022. doi:10.1016/j.bbadis.2011.02.014 PubMedCentralPubMedGoogle Scholar
  310. Venteclef N, Delerive P (2007) Interleukin-1 receptor antagonist induction as an additional mechanism for liver receptor homolog-1 to negatively regulate the hepatic acute phase response. J Biol Chem 282(7):4393–4399. doi:10.1074/jbc.M608993200 PubMedGoogle Scholar
  311. Venteclef N, Smith JC, Goodwin B, Delerive P (2006) Liver receptor homolog 1 is a negative regulator of the hepatic acute-phase response. Mol Cell Biol 26(18):6799–6807. doi:10.1128/MCB.00579-06 PubMedCentralPubMedGoogle Scholar
  312. Verma RJ, Raval PJ (1991) Cytotoxicity of aflatoxin on red blood corpuscles. Bull Environ Contam Toxicol 47(3):428–432PubMedGoogle Scholar
  313. Vinken M, Pauwels M, Ates G, Vivier M, Vanhaecke T, Rogiers V (2012) Screening of repeated dose toxicity data present in SCC(NF)P/SCCS safety evaluations of cosmetic ingredients. Arch Toxicol 86(3):405–412. doi:10.1007/s00204-011-0769-z PubMedGoogle Scholar
  314. Vogel CF, Khan EM, Leung PS et al (2014) Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-kappaB. J Biol Chem 289(3):1866–1875. doi:10.1074/jbc.M113.505578 PubMedGoogle Scholar
  315. Wang LH, Rothberg KG, Anderson RG (1993) Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. J Cell Biol 123(5):1107–1117PubMedGoogle Scholar
  316. Wang K, Shindoh H, Inoue T, Horii I (2002) Advantages of in vitro cytotoxicity testing by using primary rat hepatocytes in comparison with established cell lines. J Toxicol Sci 27(3):229–237PubMedGoogle Scholar
  317. Wang EJ, Casciano CN, Clement RP, Johnson WW (2003) Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites. Pharm Res 20(4):537–544PubMedGoogle Scholar
  318. Wang Y, Rogers PM, Su C, Varga G, Stayrook KR, Burris TP (2008) Regulation of cholesterologenesis by the oxysterol receptor, LXRalpha. J Biol Chem 283(39):26332–26339. doi:10.1074/jbc.M804808200 PubMedCentralPubMedGoogle Scholar
  319. Wang SH, Liang CT, Liu YW et al (2009) Crosstalk between activated forms of the aryl hydrocarbon receptor and glucocorticoid receptor. Toxicology 262(2):87–97. doi:10.1016/j.tox.2009.03.020 PubMedGoogle Scholar
  320. Watabe M, Nakaki T (2007) ATP depletion does not account for apoptosis induced by inhibition of mitochondrial electron transport chain in human dopaminergic cells. Neuropharmacology 52(2):536–541. doi:10.1016/j.neuropharm.2006.07.037 PubMedGoogle Scholar
  321. Watanabe N, Forman HJ (2003) Autoxidation of extracellular hydroquinones is a causative event for the cytotoxicity of menadione and DMNQ in A549-S cells. Arch Biochem Biophys 411(1):145–157PubMedCentralPubMedGoogle Scholar
  322. Watanabe M, Houten SM, Wang L et al (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Investig 113(10):1408–1418. doi:10.1172/jci200421025 PubMedCentralPubMedGoogle Scholar
  323. Watanabe K, Sakurai K, Tsuchiya Y, Yamazoe Y, Yoshinari K (2013) Dual roles of nuclear receptor liver X receptor alpha (LXRalpha) in the CYP3A4 expression in human hepatocytes as a positive and negative regulator. Biochem Pharmacol 86(3):428–436. doi:10.1016/j.bcp.2013.05.016 PubMedGoogle Scholar
  324. Watson RG, Olomu A, Clements D, Waring RH, Mitchell S, Elias E (1988) A proposed mechanism for chlorpromazine jaundice–defective hepatic sulphoxidation combined with rapid hydroxylation. J Hepatol 7(1):72–78PubMedGoogle Scholar
  325. Whelan M, Schwarz M (2013) The SEURAT-1 research strategy: proving concepts. In: Gocht T, Schwarz M (eds) Implementation of the research strategy. Towards the replacement of in vivo repeated dose systemic toxicity testing, vol 3. (self-publishing), Paris, France, pp 57–72Google Scholar
  326. Weber LW, Boll M, Stampfl A (2003) Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol 33(2):105–136. doi:10.1080/713611034 PubMedGoogle Scholar
  327. Weerapana E, Wang C, Simon GM et al (2010) Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468(7325):790–795. doi:10.1038/nature09472 PubMedCentralPubMedGoogle Scholar
  328. Wen B, Zhou M (2009) Metabolic activation of the phenothiazine antipsychotics chlorpromazine and thioridazine to electrophilic iminoquinone species in human liver microsomes and recombinant P450s. Chem Biol Interact 181(2):220–226. doi:10.1016/j.cbi.2009.05.014 PubMedGoogle Scholar
  329. Wen Y, Li W, Poteet EC et al (2011) Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem 286(18):16504–16515. doi:10.1074/jbc.M110.208447 PubMedCentralPubMedGoogle Scholar
  330. Williamson JR (1967) Glycolytic Control Mechanisms: III. Effects of iodoacetamide and fluoroacetate on glucose metabolism in the perfused rat heart. J Biol Chem 242(19):4476–4485PubMedGoogle Scholar
  331. Willson TM, Jones SA, Moore JT, Kliewer SA (2001) Chemical genomics: functional analysis of orphan nuclear receptors in the regulation of bile acid metabolism. Med Res Rev 21(6):513–522PubMedGoogle Scholar
  332. Wilmes A, Crean D, Aydin S, Pfaller W, Jennings P, Leonard MO (2011) Identification and dissection of the Nrf2 mediated oxidative stress pathway in human renal proximal tubule toxicity. Toxicol In Vitro 25(3):613–622. doi:10.1016/j.tiv.2010.12.009 PubMedGoogle Scholar
  333. Wilmes A, Leonard MO, Jennings P (2013) Nrf2 inducibility of aldo-keto reductases. Toxicol Lett 221(1):39. doi:10.1016/j.toxlet.2013.05.012 PubMedGoogle Scholar
  334. Witkowski A, Joshi AK, Smith S (2002) Mechanism of the beta-ketoacyl synthase reaction catalyzed by the animal fatty acid synthase. Biochemistry 41(35):10877–10887PubMedGoogle Scholar
  335. Witte AB, Anestal K, Jerremalm E, Ehrsson H, Arner ES (2005) Inhibition of thioredoxin reductase but not of glutathione reductase by the major classes of alkylating and platinum-containing anticancer compounds. Free Radical Biol Med 39(5):696–703. doi:10.1016/j.freeradbiomed.2005.04.025 Google Scholar
  336. Woods CG, Heuvel JP, Rusyn I (2007) Genomic profiling in nuclear receptor-mediated toxicity. Toxicol Pathol 35(4):474–494. doi:10.1080/01926230701311351 PubMedGoogle Scholar
  337. Xia W, Wang Z, Wang Q et al (2009) Roles of NAD(+)/NADH and NADP(+)/NADPH in cell death. Curr Pharm Des 15(1):12–19PubMedGoogle Scholar
  338. Xu JJ, Henstock PV, Dunn MC, Smith AR, Chabot JR, de Graaf D (2008) Cellular imaging predictions of clinical drug-induced liver injury. Toxicol Sci 105(1):97–105. doi:10.1093/toxsci/kfn109 PubMedGoogle Scholar
  339. Yang SY, Schulz H (1983) The large subunit of the fatty acid oxidation complex from Escherichia coli is a multifunctional polypeptide. Evidence for the existence of a fatty acid oxidation operon (fad AB) in Escherichia coli. J Biol Chem 258(16):9780–9785PubMedGoogle Scholar
  340. Yeager RL, Reisman SA, Aleksunes LM, Klaassen CD (2009) Introducing the “TCDD-inducible AhR-Nrf2 gene battery”. Toxicol Sci 111(2):238–246. doi:10.1093/toxsci/kfp115 PubMedCentralPubMedGoogle Scholar
  341. Yew WW, Leung CC (2006) Antituberculosis drugs and hepatotoxicity. Respirology 11(6):699–707. doi:10.1111/j.1440-1843.2006.00941.x PubMedGoogle Scholar
  342. Yew WW, Leung CC (2007) Antituberculosis drugs and hepatotoxicity. Am J Respir Crit Care Med 175(8):858; author reply 858–859 doi:10.1164/ajrccm.175.8.858a
  343. Yoshii K, Kobayashi K, Tsumuji M, Tani M, Shimada N, Chiba K (2000) Identification of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human liver microsomes. Life Sci 67(2):175–184PubMedGoogle Scholar
  344. Yoshikawa T, Ide T, Shimano H et al (2003) Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling. Mol Endocrinol 17(7):1240–1254. doi:10.1210/me.2002-0190 PubMedGoogle Scholar
  345. Zechner R, Zimmermann R, Eichmann TO et al (2012) FAT SIGNALS–lipases and lipolysis in lipid metabolism and signaling. Cell Metab 15(3):279–291. doi:10.1016/j.cmet.2011.12.018 PubMedCentralPubMedGoogle Scholar
  346. Zhang ZY, Davis JP, Van Etten RL (1992) Covalent modification and active site-directed inactivation of a low molecular weight phosphotyrosyl protein phosphatase. Biochemistry 31(6):1701–1711PubMedGoogle Scholar
  347. Zhang Y, Yin L, Anderson J et al (2010) Identification of novel pathways that control farnesoid X receptor-mediated hypocholesterolemia. J Biol Chem 285(5):3035–3043. doi:10.1074/jbc.M109.083899 PubMedCentralPubMedGoogle Scholar
  348. Zhao C, Dahlman-Wright K (2010) Liver X receptor in cholesterol metabolism. J Endocrinol 204(3):233–240. doi:10.1677/JOE-09-0271 PubMedGoogle Scholar
  349. Zhao F, Xie P, Jiang J, Zhang L, An W, Zhan Y (2014) The effect and mechanism of tamoxifen-induced hepatocyte steatosis in vitro. Int J Mol Sci 15(3):4019–4030. doi:10.3390/ijms15034019 PubMedCentralPubMedGoogle Scholar
  350. Zhou J, Zhai Y, Mu Y et al (2006) A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway. J Biol Chem 281(21):15013–15020. doi:10.1074/jbc.M511116200 PubMedCentralPubMedGoogle Scholar
  351. Zhou J, Febbraio M, Wada T et al (2008) Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 134(2):556–567. doi:10.1053/j.gastro.2007.11.037 PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Paul Jennings
    • 1
  • Michael Schwarz
    • 2
  • Brigitte Landesmann
    • 3
  • Silvia Maggioni
    • 4
  • Marina Goumenou
    • 5
  • David Bower
    • 6
  • Martin O. Leonard
    • 7
  • Jeffrey S. Wiseman
    • 8
  1. 1.Division of Physiology, Department of Physiology and Medical PhysicsMedical University of InnsbruckInnsbruckAustria
  2. 2.Institute of Experimental and Clinical Pharmacology and Toxicology, Department of ToxicologyUniversity of TuebingenTuebingenGermany
  3. 3.Systems Toxicology Unit and the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Institute for Health and Consumer Protection, Joint Research CentreEuropean CommissionIspraItaly
  4. 4.Department of Environmental Health SciencesIstituto di Ricerche Farmacologiche Mario NegriMilanItaly
  5. 5.European Food Safety AuthorityParmaItaly
  6. 6.Leadscope, Inc.ColumbusUSA
  7. 7.Centre for Radiation, Chemical and Environmental HazardsPublic Health EnglandDidcotUK
  8. 8.Pharmatrope, Ltd.DowningtownUSA

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