INDUCTION OF VARIOUS CYTOCHROMES CYP2B, CYP2C AND CYP3A BY PHENOBARBITONE IN NONHUMAN-PRIMATES

被引：27

作者：

JONES, CR ^{[1
]}

GUENGERICH, FP ^{[1
]}

RICE, JM ^{[1
]}

LUBET, RA ^{[1
]}

机构：

[1] PRI DYNCORP,BIOL CARCINOGENESIS & DEV PROGRAM,FREDERICK,MD 21702

来源：

PHARMACOGENETICS | 1992年 / 2卷 / 04期

关键词：

D O I：

10.1097/00008571-199208000-00003

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Male and female patas (Erythrocebus patas) and cynomolgus (Macaca fascicularis) monkeys were treated with phenobarbitone (PB) and examined for the induction of various cytochrome P450 (P450)-mediated drug metabolizing enzymes. Hydroxylation of testosterone at the 6beta, 2beta, and 15beta positions, metabolites normally associated with CYP3A P450s increased 2- to 5-fold in PB-treated animals. Induction of this P450 family was confirmed by the use of polyclonal antisera directed against the human CYP3A enzymes which inhibited both induced and constitutive 6beta- and 15beta-hydroxylase activities in both species of monkeys. The enzymatic activities testosterone 16beta-hydroxylation, pentoxyresorufin O-dealkylation [PROD], and benzyloxyresorufin O-dealkylation [BZROD] typically associated with the rodent CYP2B subfamily in rodents were also examined. Testosterone 16beta-hydroxylation activity was highly induced up to 15-fold in both species of monkeys to maximal levels similar to those induced in PB-treated male rats. BZROD was similarly induced up to 10-fold in both species of monkeys, but the maximal levels of BZROD achieved were substantially lower than those obtained in PB-treated rats. Finally, PROD yielded an idiosyncratic response showing substantial induction (> 30-fold) in certain patas monkeys (4 out of 8) but minimal (< 5-fold) induction in the other patas monkeys (4 out of 8) or any of the cynomolgus monkeys (0 out of 8). Immunodetection of various cytochromes using polyclonal antisera directed against rat cytochromes confirmed the induction of CYP3A proteins as well as the induction of protein(s) immunologically cross-reactive with rat CYP2B P450s. BZROD, PROD, or testosterone 16beta-hydroxylase activities, were not inhibited by antibody to CYP3A P450s. However, high concentrations of polyclonal antiserum directed against rat CYP2B inhibited all three activities in PB-induced patas monkeys. In contrast, this antiserum failed to inhibit the hydroxylation of testosterone at the 6beta or 2beta positions. Induction of the CYP2C subfamily was observed by immunochemical detection. Interestingly, induction of this subfamily appeared to be more pronounced in cynomolgus than in patas monkeys. Finally, we failed to observe significant sex-dependent differences in P450-mediated enzymatic activities in either control or induced monkeys. These results confirm the induction of a similar spectrum of P450 proteins by PB in non-human primates to that which has previously been observed in rodents.

引用

页码：160 / 172

页数：13

共 33 条

[1]

Barry M., Feely J., Enzyme induction and inhibition, Pharmacol Ther, 48, pp. 71-94, (1990)

[2]

Bloomer J.R., Porphyrin metabolism, The Liver: Biology and Pathobiology, pp. 333-345, (1982)

[3]

Bradford M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding, Anal Biochem, 72, pp. 248-254, (1976)

[4]

Breckenridge A.M., Orme ML'E. Clinical implications of enzyme induction, Ann NY Acad Sci, 179, pp. 421-431, (1971)

[5]

Dematteis F., Toxicological aspects of liver heme biosynthesis, Sem Hematol, 25, pp. 321-329, (1988)

[6]

Ding V.-H., Cameron R., Pickett C.B., Regulation of microsomal, xenobiotic epoxide hydrolase messenger RNA in persistent hepatocyte nodules and hepatomas induced by chemical carcinogens, Cancer Res, 50, pp. 256-260, (1990)

[7]

Diwan B.A., Rice J.M., Nims R.W., Lubet R.A., Hu H., Ward J.M., P450 enzyme induction by 5-ethyl-5-phenylhydantoin and 5,5-di- ethylhydantoin, analogues of barbiturate tumor promoters phenobarbital and barbital, and promotion of liver and thyroid carcinogenesis initiated by N-nitrosodiethylamine in rats, Cancer Res, 48, pp. 2492-2497, (1988)

[8]

Forrester L.M., Henderson C.J., Glancey M.J., Back D.J., Park B.K., Ball S.E., Kitteringham N.R., Mc Laren A.W., Miles J.S., Skett P., Wolf C.R., Relative expression of cytochrome P450 isoenzymes in human liver and association with the metabolism of drugs and xenobiotics, Biochem J, 281, pp. 359-368, (1992)

[9]

Gilman A., Drugs effective in the therapy of epilepsies, The Pharmacological Basis of Therapeutics, VII Edition, pp. 446-473, (1985)

[10]

Guengerich F.P., Martin M.V., Beaune P.H., Kremers P., Wolff T., Waxman D.J., Characterization of rat and human liver microsomal cytochrome P450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism, J Biol Chem, 261, pp. 5051-5060, (1986)

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