Advertisement

Archives of Toxicology

, Volume 82, Issue 12, pp 909–921 | Cite as

Pharmacologic profiling of human and rat cytochrome P450 1A1 and 1A2 induction and competition

  • Walter M. A. WesterinkEmail author
  • Joe C. R. Stevenson
  • Willem G. E. J. Schoonen
Toxicokinetics and Metabolism

Abstract

Strong activation of the AhR can lead to various toxic effects such as (non-genotoxic) carcinogenicity. Moreover, drug–drug interactions by non- or competitive inhibition of CYP1A1 and 1A2 may cause adverse side effects. Normally the majority of toxicity studies are performed in rats, while for the prediction of human toxicity human AhR activation and CYP1A competition should be studied. The present study focused on the deselection of strong AhR activators and/or CYP1A inducers and (non-)competitive inhibitors in the early phase of drug development, as well as on species differences between humans and rats. Induction studies were performed in the human HepG2 and rat H4IIE cell lines. A set of 119 compounds, including known AhR ligands were tested. CYP1A induction was observed for 24 compounds. In H4IIE cells, more compounds showed induction and most EC50 values were below those of HepG2 cells. Species specific CYP1A induction in H4IIE and HepG2 cells was obtained for eight and three compounds, respectively. The same compounds except four in-house NCEs were used to study differences between CYP1A1 and 1A2 competition in human and rat supersomes. Of the 115 compounds 46 showed CYP1A1 competition. Competition was human and rat specific for 12 and 10 compounds, respectively. CYP1A2 competition was observed for 37 compounds of which 14 and 3 compounds showed human and rat specific inhibition, respectively. In conclusion, for several compounds species differences between CYP1A induction and competition in human and rat were found. Therefore, parallel screening in both species might be a very useful strategy.

Keywords

Aryl hydrocarbon receptor CYP1A Induction Competition HepG2 H4IIE 

References

  1. Aluru N, Vuori K, Vijayan MM (2005) Modulation of Ah receptor and CYP1A1 expression by alpha-naphthoflavone in rainbow trout hepatocytes. Comp Biochem Physiol C Toxicol Pharmacol 141:40–49PubMedCrossRefGoogle Scholar
  2. Bertazzi PA, Bernucci I, Brambilla G, Consonni D, Pesatori AC (1998) The Seveso studies on early and long-term effects of dioxin exposure: a review. Environ Health Perspect 106(Suppl 2):625–633PubMedCrossRefGoogle Scholar
  3. Bogaards JJ, Bertrand M, Jackson P, Oudshoorn MJ, Weaver RJ, van Bladeren PJ, Walther B (2000) Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man. Xenobiotica 30:1131–1152PubMedCrossRefGoogle Scholar
  4. Carver LA, Jackiw V, Bradfield CA (1994) The 90-kDa heat shock protein is essential for Ah receptor signaling in a yeast expression system. J Biol Chem 269:30109–30112PubMedGoogle Scholar
  5. Chen YH, Tukey RH (1996) Protein kinase C modulates regulation of the CYP1A1 gene by the aryl hydrocarbon receptor. J Biol Chem 271:26261–26266PubMedCrossRefGoogle Scholar
  6. Danie WA, Syrek M, Rylko Z, Wojcikowski J (2001) Effects of antidepressant drugs on the activity of cytochrome P-450 measured by caffeine oxidation in rat liver microsomes. Pol J Pharmacol 53:351–357PubMedGoogle Scholar
  7. Delescluse C, Ledirac N, Li R, Piechocki MP, Hines RN, Gidrol X, Rahmani R (2001) Induction of cytochrome P450 1A1 gene expression, oxidative stress, and genotoxicity by carbaryl and thiabendazole in transfected human HepG2 and lymphoblastoid cells. Biochem Pharmacol 61:399–407PubMedCrossRefGoogle Scholar
  8. Diaz D, Fabre I, Daujat M, Saint AB, Bories P, Michel H, Maurel P (1990) Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology 99:737–747PubMedGoogle Scholar
  9. Drahushuk AT, McGarrigle BP, Larsen KE, Stegeman JJ, Olson JR (1998) Detection of CYP1A1 protein in human liver and induction by TCDD in precision-cut liver slices incubated in dynamic organ culture. Carcinogenesis 19:1361–1368PubMedCrossRefGoogle Scholar
  10. Dvorak Z, Vrzal R, Henklova P, Jancova P, Anzenbacherova E, Maurel P, Svecova L, Pavek P, Ehrmann J, Havlik R, Bednar P, Lemr K, Ulrichova J (2008) JNK inhibitor SP600125 is a partial agonist of human aryl hydrocarbon receptor and induces CYP1A1 and CYP1A2 genes in primary human hepatocytes. Biochem Pharmacol 75:580–588PubMedCrossRefGoogle Scholar
  11. Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ (1996) Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 140:173–179PubMedCrossRefGoogle Scholar
  12. Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, Sweeney MH, Greife AL, Dill PA, Steenland K, Suruda AJ (1991) Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N Engl J Med 324:212–218PubMedGoogle Scholar
  13. Flaveny C, Reen RK, Kusnadi A, Perdew GH (2008) The mouse and human Ah receptor differ in recognition of LXXLL motifs. Arch Biochem Biophys: 471:215–223CrossRefGoogle Scholar
  14. Hahn ME (2002) Aryl hydrocarbon receptors: diversity and evolution. Chem Biol Interact 141:131–160PubMedCrossRefGoogle Scholar
  15. Hazinski TA, Noisin E, Hamon I, DeMatteo A (1995) Sheep lung cytochrome P4501A1 (CYP1A1): cDNA cloning and transcriptional regulation by oxygen tension. J Clin Invest 96:2083–2089PubMedCrossRefGoogle Scholar
  16. Hecht SS (1998) Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem Res Toxicol 11:559–603PubMedCrossRefGoogle Scholar
  17. Hu W, Sorrentino C, Denison MS, Kolaja K, Fielden MR (2007) Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol Pharmacol 71:1475–1486PubMedCrossRefGoogle Scholar
  18. Jack PL, Brookes P (1981) The distribution of benzo(a) pyrene DNA adducts in mammalian chromatin. Nucleic Acids Res 9:5533–5552PubMedCrossRefGoogle Scholar
  19. Long WP, Pray-Grant M, Tsai JC, Perdew GH (1998) Protein kinase C activity is required for aryl hydrocarbon receptor pathway-mediated signal transduction. Mol Pharmacol 53:691–700PubMedGoogle Scholar
  20. Lu C, Li AP (2001) Species comparison in P450 induction: effects of dexamethasone, omeprazole, and rifampin on P450 isoforms 1A and 3A in primary cultured hepatocytes from man, Sprague-Dawley rat, minipig, and beagle dog. Chem Biol Interact 134:271–281PubMedCrossRefGoogle Scholar
  21. Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H (1991) Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 338:959–964PubMedCrossRefGoogle Scholar
  22. Murk AJ, Legler J, Denison MS, Giesy JP, van de Guchte C, Brouwer A (1996) Chemical-activated luciferase gene expression (CALUX): a novel in vitro bioassay for Ah receptor active compounds in sediments and pore water. Fundam Appl Toxicol 33:149–160PubMedCrossRefGoogle Scholar
  23. Olinga P, Elferink MG, Draaisma AL, Merema MT, Castell JV, Perez G, Groothuis GM (2008) Coordinated induction of drug transporters and phase I and II metabolism in human liver slices Eur J Pharm Sci 33:380–389Google Scholar
  24. Paajarvi G, Viluksela M, Pohjanvirta R, Stenius U, Hogberg J (2005) TCDD activates Mdm2 and attenuates the p53 response to DNA damaging agents. Carcinogenesis 26:201–208PubMedCrossRefGoogle Scholar
  25. Paine MF, Schmiedlin-Ren P, Watkins PB (1999) Cytochrome P-450 1A1 expression in human small bowel: interindividual variation and inhibition by ketoconazole. Drug Metab Dispos 27:360–364PubMedGoogle Scholar
  26. Peters AK, Leonards PE, Zhao B, Bergman A, Denison MS, Van den Berg M (2006) Determination of in vitro relative potency (REP) values for mono-ortho polychlorinated biphenyls after purification with active charcoal. Toxicol Lett 165:230–241PubMedCrossRefGoogle Scholar
  27. Pongratz I, Mason GG, Poellinger L (1992a) Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor. Evidence that the dioxin receptor functionally belongs to a subclass of nuclear receptors which require hsp90 both for ligand binding activity and repression of intrinsic DNA binding activity. J Biol Chem 267:13728–13734PubMedGoogle Scholar
  28. Pongratz I, Mason GG, Poellinger L (1992b) Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor. Evidence that the dioxin receptor functionally belongs to a subclass of nuclear receptors which require hsp90 both for ligand binding activity and repression of intrinsic DNA binding activity. J Biol Chem 267:13728–13734PubMedGoogle Scholar
  29. Postlind H, Vu TP, Tukey RH, Quattrochi LC (1993) Response of human CYP1-luciferase plasmids to 2,3,7,8-tetrachlorodibenzo-p-dioxin and polycyclic aromatic hydrocarbons. Toxicol Appl Pharmacol 118:255–262PubMedCrossRefGoogle Scholar
  30. Pushparajah DS, Umachandran M, Nazir T, Plant KE, Plant N, Lewis DF, Ioannides C (2008) Up-regulation of CYP1A/B in rat lung and liver, and human liver precision-cut slices by a series of polycyclic aromatic hydrocarbons; association with the Ah locus and importance of molecular size. Toxicol In Vitro 22:128–145PubMedCrossRefGoogle Scholar
  31. Ray SS, Swanson HI (2004) Dioxin-induced immortalization of normal human keratinocytes and silencing of p53 and p16INK4a. J Biol Chem 279:27187–27193PubMedCrossRefGoogle Scholar
  32. Roymans D, Annaert P, Van Houdt J, Weygers A, Noukens J, Sensenhauser C, Silva J, Van Looveren C, Hendrickx J, Mannens G, Meuldermans W (2005) Expression and induction potential of cytochromes P450 in human cryopreserved hepatocytes. Drug Metab Dispos 33:1004–1016PubMedCrossRefGoogle Scholar
  33. Schoonen WG, de Roos JA, Westerink WM, Debiton E (2005a) Cytotoxic effects of 110 reference compounds on HepG2 cells and for 60 compounds on HeLa, ECC-1 and CHO cells. II mechanistic assays on NAD(P) H, ATP and DNA contents. Toxicol In Vitro 19:491–503PubMedCrossRefGoogle Scholar
  34. Schoonen WG, Westerink WM, de Roos JA, Debiton E (2005b) 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 19:505–516PubMedCrossRefGoogle Scholar
  35. Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, Kume H, Mimura J, Fujii-Kuriyama Y, Ishikawa T (2000) Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci USA 97:779–782PubMedCrossRefGoogle Scholar
  36. Shinkyo R, Sakaki T, Ohta M, Inouye K (2003) Metabolic pathways of dioxin by CYP1A1: species difference between rat and human CYP1A subfamily in the metabolism of dioxins. Arch Biochem Biophys 409:180–187PubMedCrossRefGoogle Scholar
  37. Silkworth JB, Koganti A, Illouz K, Possolo A, Zhao M, Hamilton SB (2005) Comparison of TCDD and PCB CYP1A induction sensitivities in fresh hepatocytes from human donors, sprague-dawley rats, and rhesus monkeys and HepG2 cells. Toxicol Sci 87:508–519PubMedCrossRefGoogle Scholar
  38. Sonneveld E, Jonas A, Meijer OC JA, Brouwer, van der Burg B (2007) Glucocorticoid-enhanced expression of dioxin target genes through regulation of the rat aryl hydrocarbon receptor. Toxicol Sci 99:455–469PubMedCrossRefGoogle Scholar
  39. Stresser DM, Turner SD, Blanchard AP, Miller VP, Crespi CL (2002) Cytochrome P450 fluorometric substrates: identification of isoform-selective probes for rat CYP2D2 and human CYP3A4. Drug Metab Dispos 30:845–852PubMedCrossRefGoogle Scholar
  40. Wassenberg DM, Di Giulio RT (2004) Synergistic embryotoxicity of polycyclic aromatic hydrocarbon aryl hydrocarbon receptor agonists with cytochrome P4501A inhibitors in Fundulus heteroclitus. Environ Health Perspect 112:1658–1664PubMedGoogle Scholar
  41. Westerink WM, Schoonen WG (2007) Cytochrome P450 enzyme levels in HepG2 cells and cryopreserved primary human hepatocytes and their induction in HepG2 cells. Toxicol In Vitro 21:1581–1591PubMedCrossRefGoogle Scholar
  42. White IN (1988) A continuous fluorometric assay for cytochrome P-450-dependent mixed function oxidases using 3-cyano-7-ethoxycoumarin. Anal Biochem 172:304–310PubMedCrossRefGoogle Scholar
  43. Whitelaw ML, McGuire J, Picard D, Gustafsson JA, Poellinger L (1995) Heat shock protein hsp90 regulates dioxin receptor function in vivo. Proc Natl Acad Sci USA 92:4437–4441PubMedCrossRefGoogle Scholar
  44. Wu ZL, Huang SL, Ou-Yang DS, Xu ZH, Xie HG, Zhou HH (1998) Clomipramine N-demethylation metabolism in human liver microsomes. Zhongguo Yao Li Xue Bao 19:433–436PubMedGoogle Scholar
  45. Xiao Z, Hao Y, Liu B, Qian L (2002) Indirubin and meisoindigo in the treatment of chronic myelogenous leukemia in China. Leuk Lymphoma 43:1763–1768PubMedCrossRefGoogle Scholar
  46. Yoshimoto K, Echizen H, Chiba K, Tani M, Ishizaki T (1995) Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers-N-desisopropylation is mediated mainly by CYP1A2. Br J Clin Pharmacol 39:421–431PubMedGoogle Scholar
  47. Zeiger M, Haag R, Hockel J, Schrenk D, Schmitz HJ (2001) Inducing effects of dioxin-like polychlorinated biphenyls on CYP1A in the human hepatoblastoma cell line HepG2, the rat hepatoma cell line H4IIE, and rat primary hepatocytes: comparison of relative potencies. Toxicol Sci 63:65–73PubMedCrossRefGoogle Scholar
  48. Zober A, Messerer P, Huber P (1990) Thirty-four-year mortality follow-up of BASF employees exposed to 2,3,7,8-TCDD after the 1953 accident. Int Arch Occup Environ Health 62:139–157PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Walter M. A. Westerink
    • 1
    Email author
  • Joe C. R. Stevenson
    • 1
  • Willem G. E. J. Schoonen
    • 1
  1. 1.Department of PharmacologyNV Organon, a part of Schering-Plough CorporationOssThe Netherlands

Personalised recommendations