Strong Induction of Cytochrome P450 1A/3A, But not P450 2B, in Cultured Hepatocytes from Common Marmosets and Cynomolgus Monkeys by Typical Human P450 Inducing Agents.

Drug metabolism letters Pub Date : 2017-01-01 DOI:10.2174/1872312810666161114144412

Shotaro Uehara, Y. Uno, Takako Suzuki, Takashi Inoue, M. Utoh, E. Sasaki, H. Yamazaki

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引用次数: 12

Abstract

BACKGROUND Common marmosets (Callithrix jacchus) and cynomolgus monkeys (Macaca fascicularis) are used as non-human primate models in preclinical studies for drug development. OBJECTIVE The assessment of P450 induction in hepatocytes from marmosets and cynomolgus monkeys was performed using typical P450 inducers. METHODS Induction of cytochrome P450 1-4 family enzymes was analyzed in two lots of cultured hepatocytes from common marmosets and cynomolgus monkeys after 24-h treatment with typical human P450 inducing agents by real-time reverse transcription-polymerase chain reaction. RESULTS Marmoset P450 3A4 mRNA and P450 2C8/2C19 mRNA in hepatocytes were strongly (>10- fold) and weakly (>2) induced by rifampicin, respectively. Marmoset 1A1 and 1A2 mRNA were induced strongly (>200-fold) by β-naphthoflavone and omeprazole. Marmoset P450 2B6 mRNA was induced (~5-fold) by a constitutive androstane receptor agonist, but not by phenobarbital. Cynomolgus monkey P450 3A4 mRNA and P450 1A1 mRNA in cultured hepatocytes were also induced by rifampicin and omeprazole, respectively, but P450 2B6 mRNA was not induced by phenobarbital. CONCLUSION These results indicate that P450 1A/3A induction by typical human P450 inducers in hepatocytes from marmosets and/or cynomolgus monkeys are similar to those of humans (except for P450 2B induction by phenobarbital in humans), suggesting that marmosets and cynomolgus monkeys might be suitable models for evaluating the drug interactions in preclinical studies.

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典型人类P450诱导剂对普通狨猴和食蟹猴肝细胞中细胞色素P450 1A/3A的诱导作用较强，但对P450 2B的诱导作用不明显。

普通狨猴(Callithrix jacchus)和食蟹猴(Macaca fascicularis)被用作非人类灵长类动物模型，用于药物开发的临床前研究。目的采用典型P450诱导剂对狨猴和食蟹猴肝细胞P450的诱导作用进行研究。方法采用实时逆转录-聚合酶链反应法，对普通狨猴和食蟹猴肝细胞经典型人P450诱导剂作用24 h后，细胞色素P450 1-4家族酶的诱导情况进行分析。结果利福平对肝细胞中smarmoset P450 3A4 mRNA和P450 2C8/2C19 mRNA的诱导作用分别为强(>0倍)和弱(>2)。β-萘黄酮和奥美拉唑对绒猴1A1和1A2 mRNA的诱导作用较强，达到200倍。狨猴P450 2B6 mRNA可被组成型雄甾受体激动剂诱导(约5倍)，而苯巴比妥则不能。利福平和奥美拉唑均能诱导食蟹猴肝细胞P450 3A4 mRNA和P450 1A1 mRNA表达，而苯巴比妥对P450 2B6 mRNA表达无诱导作用。结论典型人P450诱导剂对狨猴和食蟹猴肝细胞P450 1A/3A的诱导作用与人相似(人类苯巴比妥对P450 2B的诱导作用除外)，提示在临床前研究中，狨猴和食蟹猴可能是评估药物相互作用的合适模型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.