scbmtБИОМЕДИЦИНАJournal Biomed2074-59822713-0428Scientific center of biomedical technologies of Federal Medical and Biological Agencyscbmt-932Research ArticleСтатьиОптимизация моделирования биотрансформации лекарственных средств цитохромами CYP-системыЛаринаС. Н.noemail@neicon.ruИгнатьевИ. В.noemail@neicon.ruЧебышевН. В.noemail@neicon.ruРаменскаяГ. В.noemail@neicon.ruПасхинаО. Е.noemail@neicon.ruМосковская медицинская академия им. И.М.СеченоваRussian FederationИнститут клинической фармакологии ФГУ НЦЭСМП, МоскваRussian Federation200713022020114856Copyright © Ларина С.Н., Игнатьев И.В., Чебышев Н.В., Раменская Г.В., Пасхина О.Е., 20202020Ларина С.Н., Игнатьев И.В., Чебышев Н.В., Раменская Г.В., Пасхина О.Е.Ларина С.Н., Игнатьев И.В., Чебышев Н.В., Раменская Г.В., Пасхина О.Е.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.scbmt.ru/jour/article/view/932

Цитохромы CYP450 играют решающую роль в осуществлении I фазы биотрансформации ксе- нобиотиков (в т.ч. лекарственных средств) в организме человека и животных. Для разработки новых лекарств, оценки лекарственных взаимодействий, также как для лучшего понимания пу- тей метаболизма различных ксенобиотиков необходимо изучать метаболизм опосредован- ный цитохромами Р450. В обзоре обсуждается возможность применения разных видов жи- вотных с наиболее адекватными системами цитохромов. Различные виды, по-видимому, мо- гут быть использованы для оценки путей биотрансформации и взаимодействия лекарств опо- средованных различными системами. Для CYP1А опосредованного метаболизма возможно использование обычных модельных животных, за исключением собаки. Напротив, собака мо- жет быть удобна для моделирования CYP2D опосредованного метаболизма. Адекватными представителями для изучения CYP2С путей могут быть обезьяны. CYP3А, по-видимому, хоро- шо моделируется CYP3A29 свиней или минисвиней. Детальное изучение механизма индукции цитохромов позволяет выявить различные типы регуляции этого процесса. Регуляция индук- ции CYP450 также является в значительной мере видоспецифической. Важную роль в этом процессе играют ядерные рецепторы PXR, CAR, RXR. Выбор соответствующего модельного животного должен проводиться с учетом механизмов регуляции индукции CYP450.

биотрансформацияцитохром Р450животные-биомоделииндукцияингибированиеReferencesAnzenbacher P., Sou е ek P., Anzenba-cherov а E., et al. Presence and activity of cytochrome P450 isoforms in minipig liver microsomes. // Drug Metab. Dispositio, 26:56, 1998.Anzenbacher P., Sou е ek P., Anzenba-cherov а E., et al. Presence and activity of cytochrome P450 isoforms in minipig liver microsomes. // Drug Metab. Dispositio, 26:56, 1998.Blumberg B., Sabbagh W., Juguilon H. et.al. SXR, a novel steroid and xenobiotic sensing nuclear receptor. // Genes Dev. 12, 3195-3205, 1998.Blumberg B., Sabbagh W., Juguilon H. et.al. SXR, a novel steroid and xenobiotic sensing nuclear receptor. // Genes Dev. 12, 3195-3205, 1998.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.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.Czekaj P. Interakcje receptorow hormone tarczycy I pochodnych witamin A I D z DNA. // Post. Biol. Kom. (in Polish), 23, 261-278, 1996.Czekaj P. Interakcje receptorow hormone tarczycy I pochodnych witamin A I D z DNA. // Post. Biol. Kom. (in Polish), 23, 261-278, 1996.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.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.Dresser G.K., Spencer D.J., Bailey D.G. Pharmacokinetic-pharmacodynamic con- sequences and clinical relevance of cytochrome P450 3A4 inhibition. // Clin. Pharmacokinet., 38: 41, 2000.Dresser G.K., Spencer D.J., Bailey D.G. Pharmacokinetic-pharmacodynamic con- sequences and clinical relevance of cytochrome P450 3A4 inhibition. // Clin. Pharmacokinet., 38: 41, 2000.http://drnelson.utmem.edu/cytochrome P450.htmlhttp://drnelson.utmem.edu/cytochrome P450.htmlFrueh F., Zanger U., Meyer U. Extent and character of Phenobarbital-mediated changes in gene expression in the liver. // Mol. Pharmacol., 51, 363-369, 1997.Frueh F., Zanger U., Meyer U. Extent and character of Phenobarbital-mediated changes in gene expression in the liver. // Mol. Pharmacol., 51, 363-369, 1997.Guengerich F.P. Comparisons on catalytic selectivity of cytochrome P450 subfamily enzymes from different species. // Chem.- Biol. Interact., 106: 161, 1997.Guengerich F.P. Comparisons on catalytic selectivity of cytochrome P450 subfamily enzymes from different species. // Chem.- Biol. Interact., 106: 161, 1997.Haugen D.A., Coon M.J. Properties of elec- trophoreticallyhomogenous Phenobarbital- inducible and beta naph- thoflavone-inducible forms of liver micro- somal cytochrome P-450. // J. Biol. Chem., 251: 7929, 1976.Haugen D.A., Coon M.J. Properties of elec- trophoreticallyhomogenous Phenobarbital- inducible and beta naph- thoflavone-inducible forms of liver micro- somal cytochrome P-450. // J. Biol. Chem., 251: 7929, 1976.He J., Fulco A. A barbiturate-regulated pro- tein binding to a common sequence in the cytochrome P450 genes of rodents and bac- teria. // J. boil. Chem., 226, 7864-7869, 1991.He J., Fulco A. A barbiturate-regulated pro- tein binding to a common sequence in the cytochrome P450 genes of rodents and bac- teria. // J. boil. Chem., 226, 7864-7869, 1991.Jayyosi Z., Muc M., Erick J. et al. Catalytic and immunochemical characterization of cytochrome P450 isozyme induction in dog liver. // Fundam. Appl. Toxicol., 31: 95. 1996.Jayyosi Z., Muc M., Erick J. et al. Catalytic and immunochemical characterization of cytochrome P450 isozyme induction in dog liver. // Fundam. Appl. Toxicol., 31: 95. 1996.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.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.Kocarek T.A., Schuetz E.G., Strom S.C. et al. Comparative analysis of cytochrome P4503A induction in primary cultures of rat, rabbit and human hepatocytes. // Drug Metab. Dispos., 23, 415-421, 1995.Kocarek T.A., Schuetz E.G., Strom S.C. et al. Comparative analysis of cytochrome P4503A induction in primary cultures of rat, rabbit and human hepatocytes. // Drug Metab. Dispos., 23, 415-421, 1995.Larsen M.C., Jefcoate C.R. Phenobarbital induction of CYP2B1, CYP2B2 and CYP3A1 in rat liver, genetic differences in a common regulatory mechanism. // Arch. Biochem. Biophys., 321, 67-476, 1995.Larsen M.C., Jefcoate C.R. Phenobarbital induction of CYP2B1, CYP2B2 and CYP3A1 in rat liver, genetic differences in a common regulatory mechanism. // Arch. Biochem. Biophys., 321, 67-476, 1995.Lehmann J., McKee D., Watson M. et al. The human orphan nuclear receptor PXR is acti- vated by compounds that regulate CYP3A4 gene expression and cause drug interactions. // J. Clin. Invest., 102, 1016-102, 1998.Lehmann J., McKee D., Watson M. et al. The human orphan nuclear receptor PXR is acti- vated by compounds that regulate CYP3A4 gene expression and cause drug interactions. // J. Clin. Invest., 102, 1016-102, 1998.Mai I., Kr u ger H., Budde K. et al. Hazardous pharmacokinetic interaction of Saint John's wort (Hypericum perfora- tum) with the immunosuppressant cyclosporine. // Int. J. Clin. Pharmacol. Therapeutics, 38: 500, 2000.Mai I., Kr u ger H., Budde K. et al. Hazardous pharmacokinetic interaction of Saint John's wort (Hypericum perfora- tum) with the immunosuppressant cyclosporine. // Int. J. Clin. Pharmacol. Therapeutics, 38: 500, 2000.Mangelsdorf D.J., Evans R.M. The RXR Heterodimers and Orphan Receptors. // Cell, 83, 841-850, 1995.Mangelsdorf D.J., Evans R.M. The RXR Heterodimers and Orphan Receptors. // Cell, 83, 841-850, 1995.Miller E., Miller J.A. Mechanisms of chemical carcinogenesis. // Cancer, 47, 1055-64, 1981.Miller E., Miller J.A. Mechanisms of chemical carcinogenesis. // Cancer, 47, 1055-64, 1981.Monshouwer M., van't Klooster G.A.E., Nijmeijer S.M. et al. Characterization of cytochrome P450 isoenzymes in primary cultures of pig hepatocytes. // Toxicol. In Vitro, 12: 715, 1998.Monshouwer M., van't Klooster G.A.E., Nijmeijer S.M. et al. Characterization of cytochrome P450 isoenzymes in primary cultures of pig hepatocytes. // Toxicol. In Vitro, 12: 715, 1998.Mulling M.E., Horowitz B.Z., Linden D.H. et al. Life-threatening interaction of mibefradil and beta-blockers wih dihy- dropyridine calcium channel blockers. - JAMA. 280: 157, 1998.Mulling M.E., Horowitz B.Z., Linden D.H. et al. Life-threatening interaction of mibefradil and beta-blockers wih dihy- dropyridine calcium channel blockers. - JAMA. 280: 157, 1998.Myers M.J., Farrell D.E., Howard K.D., Kawalek J.C. Identification of multiple con- stitutive and inducible hepatic cytochrome P450 enzymes in market weight swine. // Drug Metab. Disposition, 29: 908, 2001.Myers M.J., Farrell D.E., Howard K.D., Kawalek J.C. Identification of multiple con- stitutive and inducible hepatic cytochrome P450 enzymes in market weight swine. // Drug Metab. Disposition, 29: 908, 2001.Prasad R., Prasad N., Harrel J.E. et al. Aryl hydrocarbon hydroxylase inducibility and lymphoblast formation in lung cancer patients. // Int. J. Cancer, 23, 316-320, 1979.Prasad R., Prasad N., Harrel J.E. et al. Aryl hydrocarbon hydroxylase inducibility and lymphoblast formation in lung cancer patients. // Int. J. Cancer, 23, 316-320, 1979.Quattrochi L.C., Tukey R.H. The human CYP 1A2 gene and induction by 3-methylcholan- threne. // J.Biol.Chem., 269: 6949, 1994.Quattrochi L.C., Tukey R.H. The human CYP 1A2 gene and induction by 3-methylcholan- threne. // J.Biol.Chem., 269: 6949, 1994.Ramsden R., Sommer K.M., Omie- cinski C.J. Phenobarbital induction and tissue-specific expression of the rat CYP2B2 gene in transgenic mine. //J. Biol. Chem., 268, 21722-21726, 1993.Ramsden R., Sommer K.M., Omie- cinski C.J. Phenobarbital induction and tissue-specific expression of the rat CYP2B2 gene in transgenic mine. //J. Biol. Chem., 268, 21722-21726, 1993.Roussel F., Duignan D.B., Lawton M.P. et al. Expression and characterization of canine cytochrome P450 2D15. // Arch. Biochem. Biophys., 357: 27, 1998.Roussel F., Duignan D.B., Lawton M.P. et al. Expression and characterization of canine cytochrome P450 2D15. // Arch. Biochem. Biophys., 357: 27, 1998.Schuetz E.G., Schinkel A.H., Relling M.V., Schuetz J.D. P-glycoprotein, a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. // Proc. Natl. Acad. Sci. USA, 93, 4001-4005, 1996.Schuetz E.G., Schinkel A.H., Relling M.V., Schuetz J.D. P-glycoprotein, a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. // Proc. Natl. Acad. Sci. USA, 93, 4001-4005, 1996.Schwartz P.S., Waxman D.J. Cyclophos- phamide induces caspase 9-dependent apoptosis in 9L tumor cells. // Mol. Pharmacol., 60:1268, 2001.Schwartz P.S., Waxman D.J. Cyclophos- phamide induces caspase 9-dependent apoptosis in 9L tumor cells. // Mol. Pharmacol., 60:1268, 2001.Sharer J.E., Shipley L.A., Vandenbranded M.R. et al. Comparisons of phase I and phase II in vitro hepatic enzyme activities of human, dog, rhesus monkey, and cynomol- gus monkey. // Drug metab. Disposition, 23: 1231, 1995.Sharer J.E., Shipley L.A., Vandenbranded M.R. et al. Comparisons of phase I and phase II in vitro hepatic enzyme activities of human, dog, rhesus monkey, and cynomol- gus monkey. // Drug metab. Disposition, 23: 1231, 1995.Shehin S.E., Stephenson R.O., Green-lee W.F. Transcriptional regulation of the human CYP1B1 gene. Evidence for involvement of an aryl hydrocarbon receptor response ele- ment in constitutive expression. //J.Biol.Chem., 275, 6770-6776, 2000.Shehin S.E., Stephenson R.O., Green-lee W.F. Transcriptional regulation of the human CYP1B1 gene. Evidence for involvement of an aryl hydrocarbon receptor response ele- ment in constitutive expression. //J.Biol.Chem., 275, 6770-6776, 2000.Smith G., Henderson C., Parker M. et al. 1,4- Bis [2-(3,5-dichloropyridyloxy)] benzene, an extremely potent modulator of mouse hepatic cytochrome P-450 gene expression. // Biochem. J., 289, 807-813, 1993Smith G., Henderson C., Parker M. et al. 1,4- Bis [2-(3,5-dichloropyridyloxy)] benzene, an extremely potent modulator of mouse hepatic cytochrome P-450 gene expression. // Biochem. J., 289, 807-813, 1993Sueyoshi T., Kawamoto T., Zelko I. et al. The repressed nuclear receptor CAR responds to Phenobarbital in activating the Human CYP2B6 Gene. // J. Biol.Chem., 274, 6043-6046, 1999.Sueyoshi T., Kawamoto T., Zelko I. et al. The repressed nuclear receptor CAR responds to Phenobarbital in activating the Human CYP2B6 Gene. // J. Biol.Chem., 274, 6043-6046, 1999.Synold T.W., Dussault I., Forman B.M. The orphan nuclear receptor SXR coordi- nately regulates drug metabolism and efflux. // Nat Med.;5:584-90, 2001.Synold T.W., Dussault I., Forman B.M. The orphan nuclear receptor SXR coordi- nately regulates drug metabolism and efflux. // Nat Med.;5:584-90, 2001.Thomas P.E., Kouri R.E., Hutton J.J. The genetics of aryl hydrocarbon hydroxylase induction in mice: a single gene difference between C57BL-6J and DBA-2J. // Biochem. Genet., 6, 157-68, 1972.Thomas P.E., Kouri R.E., Hutton J.J. The genetics of aryl hydrocarbon hydroxylase induction in mice: a single gene difference between C57BL-6J and DBA-2J. // Biochem. Genet., 6, 157-68, 1972.Thummel K.E., Wilkinson G.R. In vitro and in vivo drug interaction involving human CYP3A. // Annual Rev. Pharma-col. Toxicol., 38: 389, 1998.Thummel K.E., Wilkinson G.R. In vitro and in vivo drug interaction involving human CYP3A. // Annual Rev. Pharma-col. Toxicol., 38: 389, 1998.Wei P., Zhang J., Egan-Hafley M. et al. The nuclear receptor CAR mediates spe- cific xenobiotic induction of drug metabo- lism. // Nature, 407, 920-923, 2000.Wei P., Zhang J., Egan-Hafley M. et al. The nuclear receptor CAR mediates spe- cific xenobiotic induction of drug metabo- lism. // Nature, 407, 920-923, 2000.Whitlock J., Denison M. Human cytochrome P450 enzymes; in Cytochrome P450: Structure, Mechanisms and Biochemistry (Ortiz de Montellano, P., ed.) - New York, Plenum Press, pp. 367-390, 1995.Whitlock J., Denison M. Human cytochrome P450 enzymes; in Cytochrome P450: Structure, Mechanisms and Biochemistry (Ortiz de Montellano, P., ed.) - New York, Plenum Press, pp. 367-390, 1995.Yamamoto Y., Ishizuka M., Takada A., Fujita S. Cloning, tissue distribution, and function- al expression of two novel rabbit cytochrome P450 isozymes, CYP2D23 and CYP2D24. // J. Biochem. (Tokyo), 124: 503, 1998Yamamoto Y., Ishizuka M., Takada A., Fujita S. Cloning, tissue distribution, and function- al expression of two novel rabbit cytochrome P450 isozymes, CYP2D23 and CYP2D24. // J. Biochem. (Tokyo), 124: 503, 1998

The authors declare that there are no conflicts of interest present.