Skip to main content
NCBI home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;6(2):189–198. doi: 10.1111/j.1582-4934.2002.tb00186.x

Cytochromes P450 and experimental models of drug metabolism

R Zuber 1,2,✉, Eva Anzenbacherová 2, P Anzenbacher 1
PMCID: PMC6740233  PMID: 12169204

Abstract

For the development of new drugs, evaluation of drug‐drug interactions with already known compounds, as well as for better understanding of metabolism pathways of various toxicants and pollutants, we studied the drug metabolism mediated by cytochromes P450. The experimental approach is based on animal drug‐metabolising systems. From the ethical as well as rational reasons, the selection of an appropriate system is crucial. Here, it is necessary to decide on the basis of expected CYP system involved. For CYP1A‐mediated pathways, all the commonly used experimental models are appropriate except probably the dog. On the contrary, the dog seems to be suitable for modelling of processes depending on the CYP2D. With CYP2C, which is possibly the most large and complicated subfamily, the systems based on monkey (Maccacus rhesus) may be a good representative. The CYP3A seems to be well modelled by pig or minipig CYP3A29. Detailed studies on activities with individual isolated CYP forms are needed to understand in full all aspects of inter‐species differences and variations.

Keywords: cytochrome P450, drug metabolism, inter‐species differences

References

  • 1. Ortiz de Montellano P.R., (ed.), Cytochromes P450, Plenum Press, New York 1995. [Google Scholar]
  • 2. Anzenbacher P., Anzenbacherová E., Cytochromes P450 and metabolism of xeno‐biotics, Cell. Mol. Life Sci., 58: 737, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. McLean M.A., Maves S.A., Weiss K.E., Krepich S., Sligar S.G., Characterization of a cytochrome P450 from the acidothermophilic archaea Sulfolobus solfataricus, Biochem. Biophys. Res. Commun., 252: 166, 1998. [DOI] [PubMed] [Google Scholar]
  • 4. Nelson D.R., Cytochrome P450 and the individuality of species, Arch. Biochem. Biophys., 369: 1–10, 1999. [DOI] [PubMed] [Google Scholar]
  • 5. For P450 pages on Internet, start e.g. with the http://mhc.com/cytochromes/links.HTML or with http://drnelson.utmem.edu/cytochromeP450.html.
  • 6. Krishna D., Klotz U., Exrtahepatic metabolism of drugs in humans, Clin. Pharmacokinet., 26: 144, 1994. [DOI] [PubMed] [Google Scholar]
  • 7. Mandelbaum A., Pertyborn F., Martin/Facklam M., Wiesel M., Unexplained decrease of cyclosporin trough levels in a compliant renal transplant patient, Nephrol. Dialysis Transplantation, 15: 1473, 2000. [DOI] [PubMed] [Google Scholar]
  • 8. Mai I., Krüger H., Budde K., Johne A., Brockmöller J., Neumayer H.H., Roots I., Hazardous pharmacokinetic interaction of Saint John's wort (Hypericum perforatum) with the immunosuppressant cyclosporin, Int. J. Clin. Pharmacol. Therapeutics, 38: 500, 2000. [DOI] [PubMed] [Google Scholar]
  • 9. Thummel K.E., Wilkinson G.R., In vitro and in vivo drug interactions involving human CYP3A, Annual Rev. Pharmacol. Toxicol., 38: 389, 1998. [DOI] [PubMed] [Google Scholar]
  • 10. Mullins M.E., Horowitz B.Z., Linden D.H., Smith G.W., Norton R.L., Stump J., Life‐threatening interaction of mibefradil and beta‐blockers with dihydropyridine calcium channel blockers, JAMA, 280: 157, 1998. [DOI] [PubMed] [Google Scholar]
  • 11. Dresser G.K., Spencer D.J., Bailey D.G., Pharmacokinetic‐pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition, Clin. Pharmacokinet., 38: 41, 2000. [DOI] [PubMed] [Google Scholar]
  • 12. Bertz R.J., Granneman G.R., Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions, Clin. Pharmacokinet. 32: 210, 1997. [DOI] [PubMed] [Google Scholar]
  • 13. Guengerich F.P., Human cytochrome P450 enzymes. In: Ref. 1, pp. 473–535.
  • 14. Cooper D.J., Gollackner B., Sachs D.H., Will the pig solve the transplantation backlog?, Annu. Rev. Med., 53: 133, 2002. [DOI] [PubMed] [Google Scholar]
  • 15. Guengerich F.P., Comparisons on catalytic selectivity of cytochrome P450 subfamily enzymes from different species, Chem.-Biol. Interact., 106: 161, 1997. [DOI] [PubMed] [Google Scholar]
  • 16. Smith D.A., Species differences in metabolism and pharmacokinetics: Are we close to an understanding?, Drug Metabol. Revs., 23: 355, 1991. [DOI] [PubMed] [Google Scholar]
  • 17. Aleynik M.K., Lieber C.S., Dilinoleylphosphatidylcholine decreases ethanol‐induced cytochrome P450 2E1, Biochem. Biophys. Res. Commun., 288: 1047, 2001. [DOI] [PubMed] [Google Scholar]
  • 18. Lu C., Li A.P., Species comparison in cytochrome P450 induction: Effects of dexamethasone, omeprazole, and rifampine on P450 isoforms 1A and 3A in primary cultured hepatocytes form man, Sprague‐Dawley rat, minipig, and Beagle dog, Chem.-Biol. Interact. 134: 271, 2001. [DOI] [PubMed] [Google Scholar]
  • 19. Nedelcheva V., Gut I., P450 in the rat and man: Methods of investigation, substrate specifities and relevance to cancer, Xenobiotica, 24: 1151, 1994. [DOI] [PubMed] [Google Scholar]
  • 20. Strobl G.R., von Kruedener, S. , Stockigt J., Guengerich F.P., Wolff T., Development of a pharmacophore for inhibition of human liver cytochrome P450 2D6: Molecular modelling and inhibition studies, J. Med. Chem., 36: 1136, 1993. [DOI] [PubMed] [Google Scholar]
  • 21. Kobayashi K., Urashima K., Shimada T., Chiba K., Substrate specificity for rat cytochrome P450 (CYP) isoforms: Screening with cDNA‐expressed system of the rat, Biochem. Pharmacol., 63: 889, 2002. [DOI] [PubMed] [Google Scholar]
  • 22. Gonzalez F.J., Matsunaga Y., Nagata K., Meyer U.A., Nebert D.W., Pastewka J., Kozak C.A., Gillette J., Gelboin H.W., Hardwick J.P., Debrisoquine 4‐hydroxylase: Characterization of a new P450 gene subfamily., DNA, 6:149, 1987. [DOI] [PubMed] [Google Scholar]
  • 23. Quattrochi L.C., Tukey R.H., The human CYP1A2 gene and induction by 3‐methylcholanthrene, J.Biol.Chem., 269: 6949, 1994. [PubMed] [Google Scholar]
  • 24. Haugen D.A., Coon M.J., Properties of electrophoretically homogenous phenobarbitalinducible and beta naphthoflavone‐inducible forms of liver microsomal cytochrome P‐450, J. Biol. Chem., 251: 7929, 1976. [PubMed] [Google Scholar]
  • 25. Ding X., Pernecky S.J., Coon M.J., Purification and characterization of cytochrome P450 2E2 from hepatic microsomes of neonatal rabbits, Arch. Biochem. Bioiphys., 291: 270, 1991. [DOI] [PubMed] [Google Scholar]
  • 26. Schwartz P.S., Waxman D.J., Cyclophosphamide induces caspase 9‐dependent apoptosis in 9L tumor cells, Mol. Pharmacol., 60: 1268, 2001. [DOI] [PubMed] [Google Scholar]
  • 27. Waxman D.J., Attisano C., Guengerich F.P., Lapenson D.P., Cytochrome P450 steroid hormone metabolism catalyzed by human liver microsomes, Arch. Biochem. Biophys., 263: 424, 1988. [DOI] [PubMed] [Google Scholar]
  • 28. Yamamoto Y., Ishizuka M., Takada A., Fujita S., Cloning, tissue distribution, and functional expression of two novel rabbit cytochrome P450 isozymes, CYP2D23 and CYP2D24, J. Biochem. (Tokyo), 124: 503, 1998. [DOI] [PubMed] [Google Scholar]
  • 29. Bogaards J.J.P., Bertrand M., Jackson P., Oudshoorn M.J., Weaver R.J., van Bladeren P.J., Walther B., Determining the best animal model for human cytochrome P450 activities: Comparison of mouse, rat, rabbit, dog, micropig, monkey and man, Xenobiotica, 30: 1131, 2000. [DOI] [PubMed] [Google Scholar]
  • 30. Jayyosi Z., Muc M., Erick J., Thomas P.E., Kelley M., Catalytic and immunochemical characterization of cytochrome P450 isozyme induction in dog liver, Fundam. Appl. Toxicol., 31: 95, 1996. [DOI] [PubMed] [Google Scholar]
  • 31. Roussel F., Duignan D.B., Lawton M.P., Obach R.S., Strick C.S., Tweedie D.J., Expression and characterization of canine cytochrome P450 2D15, Arch. Biochem. Biophys., 357: 27, 1998. [DOI] [PubMed] [Google Scholar]
  • 32. Chauret N., Gauthier A., Martin J., Nicoll‐Griffith D.A., In vitro comparison of cytochrome P450‐mediated metabolic activities in human, dog, cat, and horse, Drug Metab. Disposition, 25: 1130, 1997. [PubMed] [Google Scholar]
  • 33. Sharer J.E., Shipley L.A., Vandenbranden M.R., Binkley S.N., Wrighton S.A., Comparisons of phase I and phase II in vitro hepatic enzyme activities of human, dog, rhesus monkey, and cynomolgus monkey, Drug Metab. Disposition, 23: 1231, 1995. [PubMed] [Google Scholar]
  • 34. Edwards R.J., Murray S., Schulz T., Neubert D., Gant T. W., Thorgeirsson S.S., Boobis A.R., Davis D.S., Contribution of CYP1A1 and CYP1A2 on the activation of heterocyclic amines in monkeys and human, Carcinogenesis, 15: 829, 1994. [DOI] [PubMed] [Google Scholar]
  • 35. Komori M., Kikuchi O., Sakuma T., Funaki J., Kitada M., Kamataki T., Molecular cloning of monkey liver cytochromes P‐450 cDNAs: Similarity of the primary sequences to human cytochromes P‐450, Biochim. Biophys. Acta, 1171: 141, 1992. [DOI] [PubMed] [Google Scholar]
  • 36. Anzenbacher P., Souèek P., Anzenbacherová E., Gut I., Hrubý K., Svoboda Z., Kvìtina J., Presence and activity of cytochrome P450 isoforms in minipig liver microsomes, Drug Metab. Disposition, 26: 56, 1998. [PubMed] [Google Scholar]
  • 37. Skaanild M.T., Friis C., Characterization of the P450 system in Goettingen minipigs, Pharmacol. Toxicol., 80 (Suppl. 2): 28, 1997. [DOI] [PubMed] [Google Scholar]
  • 38. Monshouwer M., van't Klooster G.A.E., Nijmeijer S.M., Witkamp R.F., van Miert A.S.J.P.A.M., Characterization of cytochrome P450 isoenzymes in primary cultures of pig hepatocytes, Toxicol. In Vitro, 12: 715, 1998. [DOI] [PubMed] [Google Scholar]
  • 39. Myers M.J., Farrell D.E., Howard K.D., Kawalek J.C., Identification of multiple constitutive and inducible hepatic cytochrome P450 enzymes in market weight swine, Drug Metab. Disposition, 29: 908, 2001. [PubMed] [Google Scholar]
  • 40. Hosseinpour F., Wikvall K., Porcine microsomal vitamin D3 25‐hydroxylase (CYP2D25), J. Biol. Chem., 275: 34650, 2000. [DOI] [PubMed] [Google Scholar]
  • 41. Clement B., Lomb R., Möller W., Isolation and characterization of the protein components of the liver microsomal O2‐insensitive NADH‐benzamidoxime reductase, J. Biol. Chem., 272: 19615, 1997. [DOI] [PubMed] [Google Scholar]
  • 42. Nissen P.H., Wintero A.K., Fredholm M., Mapping of porcine genes belonging to two different cytochrome P450 subfamilies, Animal Genetics, 29: 7, 1998. [DOI] [PubMed] [Google Scholar]
  • 43. Souèek P., Zuber R., Anzenbacherová E., Anzenbacher P., Guengerich F.P., Minipig cytochrome P450 3A, 2A and 2C enzymes have similar properties to human analogs, BMC Pharmacology, 1: 11, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Olsen A., Hansen K.T., Friis C., Pig hepatocytes as an in vitro model to study the regulation of human CYP3A4: prediction of drug‐drug interactions with 17β‐ethynylestradiol, Chem.-Biol. Interact., 107: 93, 1997. [DOI] [PubMed] [Google Scholar]
  • 45. Anzenbacher P., Anzenbacherová E., Zuber R., Souèek P., Guengerich F.P., Pig and minipig cytochromes P450, Drug Metab. Disposition, 30: 100, 2002. [DOI] [PubMed] [Google Scholar]
  • 46. Takemori S., Kominami S., The role of cytochromes P450 in adrenal steroidogenesis, Trends Biochem. Sci., 9: 393, 1984. [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES