Enzymatic Basis of Phase I and Phase II Drug Metabolism



Enzyme systems have evolved in humans to maintain cellular homeostasis and to facilitate the disposition of xenobiotics. These enzymes possess complementary, and sometimes overlapping, functions, a feature which can set the stage for drug–drug interactions. In this chapter, we provide an overview of the phase I and phase II families of detoxification enzymes, their potential for induction and inhibition, and the role of genetic variants in the occurrence of drug–drug interactions.


Detoxification Enzyme Constitutive Androstane Receptor Garden Cress Phosphoramide Mustard Sulindac Sulfide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ali ZK, Kim RJ and Ysla FM (2009) CYP2C9 polymorphisms: considerations in NSAID therapy. Curr Opin Drug Discov Devel 12:108–114.PubMedGoogle Scholar
  2. Anttila S, Luostarinen L, Hirvonen A, Elovaara E, Karjalainen A, Nurminen T, Hayes JD, Vainio H and Ketterer B (1995) Pulmonary expression of glutathione S-transferase M3 in lung cancer patients: association with GSTM1 polymorphism, smoking, and asbestos exposure. Cancer Res 55:3305–3309.PubMedGoogle Scholar
  3. Bachmann K, White D, Jauregui L, Schwartz JI, Agrawal NG, Mazenko R, Larson PJ and Porras AG (2003) An evaluation of the dose-dependent inhibition of CYP1A2 by rofecoxib using theophylline as a CYP1A2 probe. J Clin Pharmacol 43:1082–1090.PubMedGoogle Scholar
  4. Backman JT, Granfors MT and Neuvonen PJ (2006) Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine. Eur J Clin Pharmacol 62:451–461.PubMedGoogle Scholar
  5. Baldwin SJ, Clarke SE and Chenery RJ (1999) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol 48:424–432.PubMedGoogle Scholar
  6. Berendsen CL, Peters WH, Scheffer PG, Bouman AA, Boven E and Newling DW (1997) Glutathione S-transferase activity and subunit composition in transitional cell cancer and mucosa of the human bladder. Urology 49:644–651.PubMedGoogle Scholar
  7. Bichlmaier I, Kurkela M, Joshi T, Siiskonen A, Ruffer T, Lang H, Suchanova B, Vahermo M, Finel M and Yli-Kauhaluoma J (2007) Isoform-selective inhibition of the human UDP-glucuronosyltransferase 2B7 by isolongifolol derivatives. J Med Chem 50:2655–2664.PubMedGoogle Scholar
  8. Blevins-Primeau AS, Sun D, Chen G, Sharma AK, Gallagher CJ, Amin S and Lazarus P (2009) Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites. Cancer Res 69:1892–1900.PubMedGoogle Scholar
  9. Bu HZ (2006) A literature review of enzyme kinetic parameters for CYP3A4-mediated metabolic reactions of 113 drugs in human liver microsomes: structure–kinetics relationship assessment. Curr Drug Metab 7:231–249.PubMedGoogle Scholar
  10. Butler MA, Lang NP, Young JF, Caporaso NE, Vineis P, Hayes RB, Teitel CH, Massengill JP, Lawsen MF and Kadlubar FF (1992) Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics 2:116–127.PubMedGoogle Scholar
  11. Cashman JR and Zhang J (2006) Human flavin-containing monooxygenases. Annu Rev Pharmacol Toxicol 46:65–100.PubMedGoogle Scholar
  12. Ching MS, Blake CL, Malek NA, Angus PW and Ghabrial H (2001) Differential inhibition of human CYP1A1 and CYP1A2 by quinidine and quinine. Xenobiotica 31:757–767.PubMedGoogle Scholar
  13. Chiu TH, Chen JC, Chen LD, Lee JH and Chung JG (2004) Gypenosides inhibited N-acetylation of 2-aminofluorene, N-acetyltransferase gene expression and DNA adduct formation in human cervix epithelioid carcinoma cells (HeLa). Res Commun Mol Pathol Pharmacol 115–116:157–174.PubMedGoogle Scholar
  14. Christensen LK, Hansen JM and Kristensen M (1963) Sulphaphenazole-induced hypoglycaemic attacks in tolbutamide-treated diabetics. Lancet 2:1298–1301.PubMedGoogle Scholar
  15. Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, Shin SG and Jang IJ (2008) Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin Pharmacol Ther 83:595–600.PubMedGoogle Scholar
  16. Clarke DJ, Moghrabi N, Monaghan G, Cassidy A, Boxer M, Hume R and Burchell B (1997) Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias. Clin Chim Acta 266:63–74.PubMedGoogle Scholar
  17. Coffman BL, Rios GR, King CD and Tephly TR (1997) Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 25:1–4.PubMedGoogle Scholar
  18. Coles B and Ketterer B (1990) The role of glutathione and glutathione transferases in chemical carcinogenesis. Crit Rev Biochem Mol Biol 25:47–70.PubMedGoogle Scholar
  19. Coles BF, Anderson KE, Doerge DR, Churchwell MI, Lang NP and Kadlubar FF (2000b) Quantitative analysis of interindividual variation of glutathione S-transferase expression in human pancreas and the ambiguity of correlating genotype with phenotype. Cancer Res 60:573–579.PubMedGoogle Scholar
  20. Coles BF, Morel F, Rauch C, Huber WW, Yang M, Teitel CH, Green B, Lang NP and Kadlubar FF (2001) Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression. Pharmacogenetics 11:663–669.PubMedGoogle Scholar
  21. Coles B, Yang M, Lang NP and Kadlubar FF (2000a) Expression of hGSTP1 alleles in human lung and catalytic activity of the native protein variants towards 1-chloro-2,4-dinitrobenzene, 4-vinylpyridine and (+)-anti benzo[a]pyrene-7,8-diol-9,10-oxide. Cancer Lett 156:167–175.PubMedGoogle Scholar
  22. Conney AH (1982) Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. Cancer Res 42:4875–4917.PubMedGoogle Scholar
  23. Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI and Goldstein JA (2001) Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 11:597–607.PubMedGoogle Scholar
  24. Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS and Day CP (2007) Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 132:272–281.PubMedGoogle Scholar
  25. Dirven HA, van Ommen B and van Bladeren PJ (1996) Glutathione conjugation of alkylating cytostatic drugs with a nitrogen mustard group and the role of glutathione S-transferases. Chem Res Toxicol 9:351–360.PubMedGoogle Scholar
  26. Falany CN (1997) Enzymology of human cytosolic sulfotransferases. FASEB J 11:206–216.PubMedGoogle Scholar
  27. Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM and Lindley CM (2000) Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 28:1222–1230.PubMedGoogle Scholar
  28. Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M and LeCluyse EL (2004) Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos 32:348–358.PubMedGoogle Scholar
  29. Ferguson SS, Chen Y, LeCluyse EL, Negishi M and Goldstein JA (2005) Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha. Mol Pharmacol 68:747–757.PubMedGoogle Scholar
  30. Ferguson SS, LeCluyse EL, Negishi M and Goldstein JA (2002) Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site. Mol Pharmacol 62:737–746.PubMedGoogle Scholar
  31. Fuhr U and Rost KL (1994) Simple and reliable CYP1A2 phenotyping by the paraxanthine/caffeine ratio in plasma and in saliva. Pharmacogenetics 4:109–116.PubMedGoogle Scholar
  32. Glatt H, Boeing H, Engelke CE, Ma L, Kuhlow A, Pabel U, Pomplun D, Teubner W and Meinl W (2001) Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects. Mutat Res 482:27–40.PubMedGoogle Scholar
  33. Gonzalez FJ, Vilbois F, Hardwick JP, McBride OW, Nebert DW, Gelboin HV and Meyer UA (1988) Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Genomics 2:174–179.PubMedGoogle Scholar
  34. Grancharov K, Engelberg H, Naydenova Z, Muller G, Rettenmeier AW and Golovinsky E (2001a) Inhibition of UDP-glucuronosyltransferases in rat liver microsomes by natural mutagens and carcinogens. Arch Toxicol 75:609–612.PubMedGoogle Scholar
  35. Grancharov K, Naydenova Z, Lozeva S and Golovinsky E (2001b) Natural and synthetic inhibitors of UDP-glucuronosyltransferase. Pharmacol Ther 89:171–186.PubMedGoogle Scholar
  36. Grant DM, Blum M, Beer M and Meyer UA (1991) Monomorphic and polymorphic human arylamine N-acetyltransferases: a comparison of liver isozymes and expressed products of two cloned genes. Mol Pharmacol 39:184–191.PubMedGoogle Scholar
  37. Guillemette C (2003) Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 3:136–158.PubMedGoogle Scholar
  38. Harris RM and Waring RH (1996) Dietary modulation of human platelet phenolsulphotransferase activity. Xenobiotica 26:1241–1247.PubMedGoogle Scholar
  39. Hayes JD and Pulford DJ (1995) The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30:445–600.PubMedGoogle Scholar
  40. Hayes JD and Strange RC (2000) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 61:154–166.PubMedGoogle Scholar
  41. Hayeshi R, Mutingwende I, Mavengere W, Masiyanise V and Mukanganyama S (2007) The inhibition of human glutathione S-transferases activity by plant polyphenolic compounds ellagic acid and curcumin. Food Chem Toxicol 45:286–295.PubMedGoogle Scholar
  42. Hebbring SJ, Adjei AA, Baer JL, Jenkins GD, Zhang J, Cunningham JM, Schaid DJ, Weinshilboum RM and Thibodeau SN (2007) Human SULT1A1 gene: copy number differences and functional implications. Hum Mol Genet 16:463–470.PubMedGoogle Scholar
  43. Hofmann MH, Blievernicht JK, Klein K, Saussele T, Schaeffeler E, Schwab M and Zanger UM (2008) Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver. J Pharmacol Exp Ther 325:284–292.PubMedGoogle Scholar
  44. Huang Z, Roy P and Waxman DJ (2000) Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol 59:961–972.PubMedGoogle Scholar
  45. Hughes HB (1953) On the metabolic fate of isoniazid. J Pharmacol Exp Ther 109:444–452.PubMedGoogle Scholar
  46. Ibeanu GC, Blaisdell J, Ferguson RJ, Ghanayem BI, Brosen K, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P and Goldstein JA (1999) A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin. J Pharmacol Exp Ther 290:635–640.PubMedGoogle Scholar
  47. Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Daly AK and Goldstein JA (1998) An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics 8:129–135.PubMedGoogle Scholar
  48. Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE and Ratain MJ (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388.PubMedGoogle Scholar
  49. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF and Flockhart DA (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30–39.PubMedGoogle Scholar
  50. Johnson JA, Herring VL, Wolfe MS and Relling MV (2000) CYP1A2 and CYP2D6 4-hydroxylate propranolol and both reactions exhibit racial differences. J Pharmacol Exp Ther 294:1099–1105.PubMedGoogle Scholar
  51. Kahn GC, Boobis AR, Murray S, Brodie MJ and Davies DS (1982) Assay and characterisation of debrisoquine 4-hydroxylase activity of microsomal fractions of human liver. Br J Clin Pharmacol 13:637–645.PubMedGoogle Scholar
  52. Karjalainen MJ, Neuvonen PJ and Backman JT (2008) In vitro inhibition of CYP1A2 by model inhibitors, anti-inflammatory analgesics and female sex steroids: predictability of in vivo interactions. Basic Clin Pharmacol Toxicol 103:157–165.PubMedGoogle Scholar
  53. Kassahun K, Farrell K and Abbott F (1991) Identification and characterization of the glutathione and N-acetylcysteine conjugates of (E)-2-propyl-2,4-pentadienoic acid, a toxic metabolite of valproic acid, in rats and humans. Drug Metab Dispos 19:525–535.PubMedGoogle Scholar
  54. Khan AJ, Ruwali M, Choudhuri G, Mathur N, Husain Q and Parmar D (2009) Polymorphism in cytochrome P450 2E1 and interaction with other genetic risk factors and susceptibility to alcoholic liver cirrhosis. Mutat Res 664:55–63.PubMedGoogle Scholar
  55. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C and Watkins PB (1992) Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 90:1871–1878.PubMedGoogle Scholar
  56. Koukouritaki SB, Poch MT, Henderson MC, Siddens LK, Krueger SK, VanDyke JE, Williams DE, Pajewski NM, Wang T and Hines RN (2007) Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants. J Pharmacol Exp Ther 320:266–273.PubMedGoogle Scholar
  57. Krueger SK and Williams DE (2005) Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther 106:357–387.PubMedGoogle Scholar
  58. Krusekopf S, Roots I and Kleeberg U (2003) Differential drug-induced mRNA expression of human CYP3A4 compared to CYP3A5, CYP3A7 and CYP3A43. Eur J Pharmacol 466:7–12.PubMedGoogle Scholar
  59. Kunii T, Fukasawa T, Yasui-Furukori N, Aoshima T, Suzuki A, Tateishi T, Inoue Y and Otani K (2005) Interaction study between enoxacin and fluvoxamine. Ther Drug Monit 27:349–353.PubMedGoogle Scholar
  60. Landi S (2000) Mammalian class theta GST and differential susceptibility to carcinogens: a review. Mutat Res 463:247–283.PubMedGoogle Scholar
  61. Lasker JM, Wester MR, Aramsombatdee E and Raucy JL (1998) Characterization of CYP2C19 and CYP2C9 from human liver: respective roles in microsomal tolbutamide, S-mephenytoin, and omeprazole hydroxylations. Arch Biochem Biophys 353:16–28.PubMedGoogle Scholar
  62. Lattard V, Zhang J, Tran Q, Furnes B, Schlenk D and Cashman JR (2003) Two new polymorphisms of the FMO3 gene in Caucasian and African-American populations: comparative genetic and functional studies. Drug Metab Dispos 31:854–860.PubMedGoogle Scholar
  63. Lee AM, Jepson C, Hoffmann E, Epstein L, Hawk LW, Lerman C and Tyndale RF (2007) CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial. Biol Psychiatry 62:635–641.PubMedGoogle Scholar
  64. Lee PC, Marquardt M and Lech JJ (1998) Metabolism of nonylphenol by rat and human microsomes. Toxicol Lett 99:117–126.PubMedGoogle Scholar
  65. Lemaire G, de Sousa G and Rahmani R (2004) A PXR reporter gene assay in a stable cell culture system: CYP3A4 and CYP2B6 induction by pesticides. Biochem Pharmacol 68:2347–2358.PubMedGoogle Scholar
  66. Lhoste EF, Gloux K, De Waziers I, Garrido S, Lory S, Philippe C, Rabot S and Knasmuller S (2004) The activities of several detoxication enzymes are differentially induced by juices of garden cress, water cress and mustard in human HepG2 cells. Chem Biol Interact 150:211–219.PubMedGoogle Scholar
  67. Lim YC, Desta Z, Flockhart DA and Skaar TC (2005) Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol 55:471–478.PubMedGoogle Scholar
  68. Lim YC, Li L, Desta Z, Zhao Q, Rae JM, Flockhart DA and Skaar TC (2006) Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther 318:503–512.PubMedGoogle Scholar
  69. Liu L, Wagner CR and Hanna PE (2008) Human arylamine N-acetyltransferase 1: in vitro and intracellular inactivation by nitrosoarene metabolites of toxic and carcinogenic arylamines. Chem Res Toxicol 21:2005–2016.PubMedGoogle Scholar
  70. Lofgren S, Baldwin RM, Hiratsuka M, Lindqvist A, Carlberg A, Sim SC, Schulke M, Snait M, Edenro A, Fransson-Steen R, Terelius Y and Ingelman-Sundberg M (2008) Generation of mice transgenic for human CYP2C18 and CYP2C19: characterization of the sexually dimorphic gene and enzyme expression. Drug Metab Dispos 36:955–962.PubMedGoogle Scholar
  71. Madabushi R, Frank B, Drewelow B, Derendorf H and Butterweck V (2006) Hyperforin in St. John’s wort drug interactions. Eur J Clin Pharmacol 62:225–233.PubMedGoogle Scholar
  72. Mahgoub A, Idle JR, Dring LG, Lancaster R and Smith RL (1977) Polymorphic hydroxylation of Debrisoquine in man. Lancet 2:584–586.PubMedGoogle Scholar
  73. Masubuchi Y, Hosokawa S, Horie T, Suzuki T, Ohmori S, Kitada M and Narimatsu S (1994) Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes. The role of CYP2D6 as ring-hydroxylase and CYP1A2 as N-desisopropylase. Drug Metab Dispos 22:909–915.PubMedGoogle Scholar
  74. Matsubara T, Noracharttiyapot W, Toriyabe T, Yoshinari K, Nagata K and Yamazoe Y (2007) Assessment of human pregnane X receptor involvement in pesticide-mediated activation of CYP3A4 gene. Drug Metab Dispos 35:728–733.PubMedGoogle Scholar
  75. Mitchell SC (2008) Flavin mono-oxygenase (FMO)–the 'other' oxidase. Curr Drug Metab 9:280–284.PubMedGoogle Scholar
  76. Mori Y, Iimura K, Furukawa F, Nishikawa A, Takahashi M and Konishi Y (1995) Effect of cigarette smoke on the mutagenic activation of various carcinogens in hamster. Mutat Res 346:1–8.PubMedGoogle Scholar
  77. Nadin L and Murray M (1999) Participation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes. Biochem Pharmacol 58:1201–1208.PubMedGoogle Scholar
  78. Neff JA and Moody DE (2001) Differential N-demethylation of l-alpha-acetylmethadol (LAAM) and norLAAM by cytochrome P450s 2B6, 2C18, and 3A4. Biochem Biophys Res Commun 284:751–756.PubMedGoogle Scholar
  79. Olson JR, McGarrigle BP, Gigliotti PJ, Kumar S and McReynolds JH (1994) Hepatic uptake and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzofuran. Fundam Appl Toxicol 22:631–640.PubMedGoogle Scholar
  80. Omura T (1999) Forty years of cytochrome P450. Biochem Biophys Res Commun 266:690–698.PubMedGoogle Scholar
  81. Ozawa S, Tang YM, Yamazoe Y, Kato R, Lang NP and Kadlubar FF (1998) Genetic polymorphisms in human liver phenol sulfotransferases involved in the bioactivation of N-hydroxy derivatives of carcinogenic arylamines and heterocyclic amines. Chem Biol Interact 109:237–248.PubMedGoogle Scholar
  82. Pacifici GM (2004) Inhibition of human liver and duodenum sulfotransferases by drugs and dietary chemicals: a review of the literature. Int J Clin Pharmacol Ther 42:488–495.PubMedGoogle Scholar
  83. Pascussi JM, Gerbal-Chaloin S, Drocourt L, Maurel P and Vilarem MJ (2003) The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. Biochim Biophys Acta 1619:243–253.PubMedGoogle Scholar
  84. Peters WH, Kock L, Nagengast FM and Kremers PG (1991) Biotransformation enzymes in human intestine: critical low levels in the colon? Gut 32:408–412.PubMedGoogle Scholar
  85. Phillips IR, Dolphin CT, Clair P, Hadley MR, Hutt AJ, McCombie RR, Smith RL and Shephard EA (1995) The molecular biology of the flavin-containing monooxygenases of man. Chem Biol Interact 96:17–32.PubMedGoogle Scholar
  86. Poonkuzhali B, Chandy M, Srivastava A, Dennison D and Krishnamoorthy R (2001) Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation. Drug Metab Dispos 29:264–267.PubMedGoogle Scholar
  87. Price RA, Spielman RS, Lucena AL, Van Loon JA, Maidak BL and Weinshilboum RM (1989) Genetic polymorphism for human platelet thermostable phenol sulfotransferase (TS PST) activity. Genetics 122:905–914.PubMedGoogle Scholar
  88. Raaska K and Neuvonen PJ (2000) Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia. Eur J Clin Pharmacol 56:585–589.PubMedGoogle Scholar
  89. Racha JK, Zhao ZS, Olejnik N, Warner N, Chan R, Moore D and Satoh H (2003) Substrate dependent inhibition profiles of fourteen drugs on CYP3A4 activity measured by a high throughput LCMS/MS method with four probe drugs, midazolam, testosterone, nifedipine and terfenadine. Drug Metab Pharmacokinet 18:128–138.PubMedGoogle Scholar
  90. Rae JM, Johnson MD, Lippman ME and Flockhart DA (2001) Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther 299:849–857.PubMedGoogle Scholar
  91. Raftogianis RB, Wood TC, Otterness DM, Van Loon JA and Weinshilboum RM (1997) Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype. Biochem Biophys Res Commun 239:298–304.PubMedGoogle Scholar
  92. Ragunathan N, Dairou J, Pluvinage B, Martins M, Petit E, Janel N, Dupret JM and Rodrigues-Lima F (2008) Identification of the xenobiotic-metabolizing enzyme arylamine N-acetyltransferase 1 as a new target of cisplatin in breast cancer cells: molecular and cellular mechanisms of inhibition. Mol Pharmacol 73:1761–1768.PubMedGoogle Scholar
  93. Raucy JL, Mueller L, Duan K, Allen SW, Strom S and Lasker JM (2002) Expression and induction of CYP2C P450 enzymes in primary cultures of human hepatocytes. J Pharmacol Exp Ther 302:475–482.PubMedGoogle Scholar
  94. Rebbeck TR (1997) Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev 6:733–743.PubMedGoogle Scholar
  95. Reilly PE, Mason SR and Gillam EM (1988) Differential inhibition of human liver phenacetin O-deethylation by histamine and four histamine H2-receptor antagonists. Xenobiotica 18:381–387.PubMedGoogle Scholar
  96. Roby CA, Anderson GD, Kantor E, Dryer DA and Burstein AH (2000) St John’s Wort: effect on CYP3A4 activity. Clin Pharmacol Ther 67:451–457.PubMedGoogle Scholar
  97. Rowe JD, Nieves E and Listowsky I (1997) Subunit diversity and tissue distribution of human glutathione S-transferases: interpretations based on electrospray ionization-MS and peptide sequence-specific antisera. Biochem J 325 (Pt 2):481–486.PubMedGoogle Scholar
  98. Sahi J, Black CB, Hamilton GA, Zheng X, Jolley S, Rose KA, Gilbert D, LeCluyse EL and Sinz MW (2003) Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab Dispos 31:439–446.PubMedGoogle Scholar
  99. Schuetz JD, Kauma S and Guzelian PS (1993) Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta. J Clin Invest 92:1018–1024.PubMedGoogle Scholar
  100. Shimada T, Inoue K, Suzuki Y, Kawai T, Azuma E, Nakajima T, Shindo M, Kurose K, Sugie A, Yamagishi Y, Fujii-Kuriyama Y and Hashimoto M (2002) Arylhydrocarbon receptor-dependent induction of liver and lung cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic hydrocarbons and polychlorinated biphenyls in genetically engineered C57BL/6 J mice. Carcinogenesis 23:1199–1207.PubMedGoogle Scholar
  101. Shimada T, Yamazaki H, Mimura M, Inui Y and Guengerich FP (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414–423.PubMedGoogle Scholar
  102. Shimizu M, Yano H, Nagashima S, Murayama N, Zhang J, Cashman JR and Yamazaki H (2007) Effect of genetic variants of the human flavin-containing monooxygenase 3 on N- and S-oxygenation activities. Drug Metab Dispos 35:328–330.PubMedGoogle Scholar
  103. Sim E, Walters K and Boukouvala S (2008) Arylamine N-acetyltransferases: from structure to function. Drug Metab Rev 40:479–510.PubMedGoogle Scholar
  104. Slattery JT, Wilson JM, Kalhorn TF and Nelson SD (1987) Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in humans. Clin Pharmacol Ther 41:413–418.PubMedGoogle Scholar
  105. Snawder JE, Roe AL, Benson RW and Roberts DW (1994) Loss of CYP2E1 and CYP1A2 activity as a function of acetaminophen dose: relation to toxicity. Biochem Biophys Res Commun 203:532–539.PubMedGoogle Scholar
  106. Sun D, Sharma AK, Dellinger RW, Blevins-Primeau AS, Balliet RM, Chen G, Boyiri T, Amin S and Lazarus P (2007) Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases. Drug Metab Dispos 35:2006–2014.PubMedGoogle Scholar
  107. Swales K, Kakizaki S, Yamamoto Y, Inoue K, Kobayashi K and Negishi M (2005) Novel CAR-mediated mechanism for synergistic activation of two distinct elements within the human cytochrome P450 2B6 gene in HepG2 cells. J Biol Chem 280:3458–3466.PubMedGoogle Scholar
  108. Takeda S, Kitajima Y, Ishii Y, Nishimura Y, Mackenzie PI, Oguri K and Yamada H (2006) Inhibition of UDP-glucuronosyltransferase 2b7-catalyzed morphine glucuronidation by ketoconazole: dual mechanisms involving a novel noncompetitive mode. Drug Metab Dispos 34:1277–1282.PubMedGoogle Scholar
  109. Talalay P and Fahey JW (2001) Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. J Nutr 131:3027S–3033S.PubMedGoogle Scholar
  110. Valentini A, Biancolella M, Amati F, Gravina P, Miano R, Chillemi G, Farcomeni A, Bueno S, Vespasiani G, Desideri A, Federici G, Novelli G and Bernardini S (2007) Valproic acid induces neuroendocrine differentiation and UGT2B7 up-regulation in human prostate carcinoma cell line. Drug Metab Dispos 35:968–972.PubMedGoogle Scholar
  111. van Ommen B, Bogaards JJ, Peters WH, Blaauboer B and van Bladeren PJ (1990) Quantification of human hepatic glutathione S-transferases. Biochem J 269:609–613.PubMedGoogle Scholar
  112. Venkatakrishnan K, Von Moltke LL and Greenblatt DJ (2001) Human drug metabolism and the cytochromes P450: application and relevance of in vitro models. J Clin Pharmacol 41:1149–1179.PubMedGoogle Scholar
  113. Walle T (1996) Assays of CYP2C8- and CYP3A4-mediated metabolism of taxol in vivo and in vitro. Methods Enzymol 272:145–151.PubMedGoogle Scholar
  114. Walle T, Otake Y, Galijatovic A, Ritter JK and Walle UK (2000) Induction of UDP-glucuronosyltransferase UGT1A1 by the flavonoid chrysin in the human hepatoma cell line hep G2. Drug Metab Dispos 28:1077–1082.PubMedGoogle Scholar
  115. Walsky RL, Gaman EA and Obach RS (2005) Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol 45:68–78.PubMedGoogle Scholar
  116. Walters DG, Young PJ, Agus C, Knize MG, Boobis AR, Gooderham NJ and Lake BG (2004) Cruciferous vegetable consumption alters the metabolism of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans. Carcinogenesis 25:1659–1669.PubMedGoogle Scholar
  117. Wang H and Tompkins LM (2008) CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Curr Drug Metab 9:598–610.PubMedGoogle Scholar
  118. Wang JS, Neuvonen M, Wen X, Backman JT and Neuvonen PJ (2002) Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos 30:1352–1356.PubMedGoogle Scholar
  119. Waszkowycz B, Clark DE, Frenkel D, Li J, Murray CW, Robson B and Westhead DR (1994) PRO_LIGAND: an approach to de novo molecular design. 2. Design of novel molecules from molecular field analysis (MFA) models and pharmacophores. J Med Chem 37:3994–4002.PubMedGoogle Scholar
  120. Weber WW and Hein DW (1985) N-Acetylation pharmacogenetics. Pharmacol Rev 37:25–79.PubMedGoogle Scholar
  121. Weinshilboum RM, Otterness DM, Aksoy IA, Wood TC, Her C and Raftogianis RB (1997) Sulfation and sulfotransferases 1: Sulfotransferase molecular biology: cDNAs and genes. FASEB J 11:3–14.PubMedGoogle Scholar
  122. Yamazaki H, Suzuki M, Tane K, Shimada N, Nakajima M and Yokoi T (2000) In vitro inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human cytochrome P450 enzymes: comparison with pioglitazone and rosiglitazone. Xenobiotica 30:61–70.PubMedGoogle Scholar
  123. Yanagihara Y, Kariya S, Ohtani M, Uchino K, Aoyama T, Yamamura Y and Iga T (2001) Involvement of CYP2B6 in n-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 29:887–890.PubMedGoogle Scholar
  124. Zaher H, Buters JT, Ward JM, Bruno MK, Lucas AM, Stern ST, Cohen SD and Gonzalez FJ (1998) Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol Appl Pharmacol 152:193–199.PubMedGoogle Scholar
  125. Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH and Schwab M (2007) Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics 8:743–759.PubMedGoogle Scholar
  126. Zanger UM, Turpeinen M, Klein K and Schwab M (2008) Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 392:1093–1108.PubMedGoogle Scholar
  127. Zhang ZY, Kerr J, Wexler RS, Li HY, Robinson AJ, Harlow PP and Kaminsky LS (1997) Warfarin analog inhibition of human CYP2C9-catalyzed S-warfarin 7-hydroxylation. Thromb Res 88:389–398.PubMedGoogle Scholar
  128. Zhou SF (2008) Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab 9:310–322.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Environmental and Occupational Health, College of Public HealthUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.Department of Epidemiology, College of Public HealthUniversity of Arkansas for Medical SciencesLittle RockUSA

Personalised recommendations