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首页> 外文期刊>Life sciences >Evaluation of hepatic cytochrome P4502E1 in the species-dependent bioactivation of 4-vinylcyclohexene.
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Evaluation of hepatic cytochrome P4502E1 in the species-dependent bioactivation of 4-vinylcyclohexene.

机译：在4-乙烯基环己烯的物种依赖性生物激活中评估肝细胞色素P4502E1。

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摘要

4-Vinyl-1-cyclohexene (VCH), is converted by multiple forms of cytochrome P450 (CYP) to two monoepoxides (4-vinyl-1-cyclohexene 1,2-epoxide [VCH-1,2-epoxide], 4-vinyl-1-cyclohexene 7,8-epoxide [VCH-7,8-epoxide]), and 4-vinyl-1-cyclohexene diepoxide (VCD). A greater degree of formation of these epoxides by female B6C3F1 mice as compared to Fischer 344 rats correlates with the ovarian toxicity observed only in the mice. Understanding which isoforms of CYP are involved in VCH bioactivation will better explain the species-dependent ovotoxicity of VCH. Present studies focus on the role of CYP2E1, as this isoform is responsible for the bioactivation of several structurally related small molecular weight compounds, including 1,3-butadiene. Hepatic microsomes prepared from either mice or rats pretreated with the CYP inducer acetone demonstrated 2-fold increases in the formation of VCH-1,2-epoxide. However, incubations with microsomes from cyp2e1-deficient mice compared to those from wild type mice revealed no differences in the rates of bioactivation of VCH to the monoepoxides. Since repeated exposure to VCH is required for VCH-induced ovotoxicity, rodents were dosed with VCH for 5 or 10 d to observe effects on the hepatic concentration of CYP2E1 and/or associated activities. VCH pretreatment failed to increase the concentration of CYP2E1 or CYP2E1 activity in either species, as measured by immunoblotting analysis and p-nitrophenol hydroxylation. Based on these data, it is concluded that CYP2E1 does not play a role in the species differences between mice and rats in the bioactivation of VCH following repeated exposure to VCH. Other isoforms, such as those in CYP2A and CYP2B subfamilies, are likely involved in VCH bioactivation.
机译：4-乙烯基-1-环己烯（VCH）通过多种形式的细胞色素P450（CYP）转化为两种单环氧化物（4-乙烯基-1-环己烯1,2-环氧化物[VCH-1,2-环氧]，4-乙烯基-1-环己烯7，8-环氧[VCH-7，8-环氧]和4-乙烯基-1-环己烯二环氧（VCD）。与Fischer 344大鼠相比，雌性B6C3F1小鼠形成这些环氧化物的程度更大，这与仅在小鼠中观察到的卵巢毒性有关。了解CYP的哪些同工型参与VCH生物激活将更好地解释VCH的物种依赖性卵毒性。目前的研究集中于CYP2E1的作用，因为该同工型负责几种与结构相关的小分子量化合物（包括1,3-丁二烯）的生物活化。由用CYP诱导剂丙酮预处理的小鼠或大鼠制备的肝微粒体显示VCH-1,2-环氧化合物的形成增加了2倍。但是，与来自野生型小鼠的cyp2e1缺陷小鼠相比，用微粒体进行的温育表明VCH对单环氧化物的生物活化速率没有差异。由于VCH引起的卵毒性需要反复暴露于VCH，因此给啮齿动物服用VCH 5天或10天，以观察对CYP2E1肝浓度和/或相关活性的影响。通过免疫印迹分析和对硝基苯酚羟基化作用，VCH预处理未能增加两种物种中CYP2E1或CYP2E1活性的浓度。根据这些数据，可以得出结论，CYP2E1在反复暴露于VCH后对VCH的生物活化中的小鼠和大鼠之间的物种差异中不起作用。其他同工型，例如CYP2A和CYP2B亚家族的同工型，可能也参与了VCH的生物激活。

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