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首页> 外文期刊>Archives of Toxicology >Induction of CYP2A5 by pyrazole and its derivatives in mouse primary hepatocytes.
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Induction of CYP2A5 by pyrazole and its derivatives in mouse primary hepatocytes.

机译：吡唑及其衍生物在小鼠原代肝细胞中诱导CYP2A5。

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Mouse liver CYP2A5 is induced by several structurally unrelated compounds. In intact mouse liver, pyrazole (PYR) and 4-hydroxypyrazole (4-OH) induce selectively the expression of CYP2A5 while expression of other CYPs is decreased. In this study we exposed mouse primary hepatocytes to PYR, 4-OH, 4-methylpyrazole (4Me; 0.1-20 mM) and 4-iodopyrazole (4-I; 0.1-5.0 mM). PYR and its derivatives increased coumarin 7-hydroxylase activity, with 4-1 and 4-OH being the strongest inducers, by 114-fold and 41-fold, respectively. However, only 4-1 treatment increased markedly the CYP2A5 protein content. CYP2B9/10-mediated pentoxyresorufin O-deethylase activity (PROD) was decreased by 80% by 4-Me and 4-1, and by 50% by 4-OH while PYR had no marked effect. PYR and 4-Me increased 2- to 3-fold the CYPA1/2-mediated ethoxyresorufin O-deethylase activity (EROD) while 4-OH and 4-1 had no marked effect on this enzyme. The time of exposure markedly affected the inducibility of 4-OH such that induction was 7-fold stronger when it was added to the incubation medium 24 h after the isolation of hepatocytes compared to exposure 3 h after their isolation. Cimetidine prevented the induction of coumarin 7-hydroxylase activity by PYR and 4-OH by 46 and 74%, respectively indicating that their effects on the expression of CYP2A5 are, at least partly, mediated via their metabolites. The data demonstrate that the regulation of CYP2A5 is different from other monooxygenases and that the effects of pyrazole and its derivatives are different in vivo and in vitro. Also, the timing of exposure markedly affects the inducibility of 4-OH in hepatocytes.
机译：小鼠肝脏CYP2A5由几种结构上无关的化合物诱导。在完整的小鼠肝脏中，吡唑（PYR）和4-羟基吡唑（4-OH）选择性诱导CYP2A5的表达，而其他CYP的表达降低。在这项研究中，我们将小鼠原代肝细胞暴露于PYR，4-OH，4-甲基吡唑（4Me; 0.1-20 mM）和4-碘吡唑（4-I; 0.1-5.0 mM）。 PYR及其衍生物提高了香豆素7-羟化酶的活性，其中4-1和4-OH是最强的诱导剂，分别增加了114倍和41倍。然而，只有4-1处理显着增加CYP2A5蛋白含量。 CYP2B9 / 10介导的戊氧基间苯二酚的O-脱乙基酶活性（PROD）被4-Me和4-1降低了80％，被4-OH降低了50％，而PYR没有明显的作用。 PYR和4-Me使CYPA1 / 2介导的乙氧基间苯二酚O-脱乙基酶活性（EROD）增加2到3倍，而4-OH和4-1对这种酶没有明显影响。暴露时间显着影响了4-OH的诱导能力，因此，与分离后3 h的暴露相比，在分离肝细胞后24 h将其添加到培养液中的诱导强度要强7倍。西咪替丁分别通过PYR和4-OH阻止香豆素7-羟化酶活性的诱导分别达到46％和74％，这表明它们对CYP2A5表达的影响至少部分是通过其代谢产物介导的。数据表明CYP2A5的调节与其他单加氧酶不同，吡唑及其衍生物的体内和体外作用也不同。同样，暴露的时间明显影响了肝细胞中4-OH的诱导性。

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