Evaluation of hepatic cytochrome P4502E1 in the species-dependent bioactivation of 4-vinylcyclohexene.
Evaluation of hepatic cytochrome P4502E1 in the species-dependent bioactivation of 4-vinylcyclohexene.
复制标题
肝细胞色素 P4502E1 在 4-乙烯基环己烯物种依赖性生物活化中的评估。
DOI：
10.1016/s0024-3205(01)01170-5
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发表时间：
2001
期刊：
影响因子：
6.1
通讯作者：
Sipes,IG
中科院分区：
文献类型：
--
作者：
Fontaine,SM;Hoyer,PB;Sipes,IG
4-乙烯基-1-环己烯(VCH)被多种形式的细胞色素P450(CYP)转化为两个单环氧化物(4-乙烯-1-环己烯1，2-环氧化物[VCH-1，2-环氧化物]，4-乙烯-1-环己烯7，8-环氧化物[VCH-7，8-环氧化物])和4-乙烯-1-环己烯二环氧化物(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高，这与只在小鼠中观察到的卵巢毒性有关。了解哪些CYP亚型参与了VCH的生物激活，将更好地解释VCH的物种依赖性卵毒性。目前的研究主要集中在CYP2E1的作用上，因为这种异构体负责几种结构相关的小分子化合物的生物活性，包括1，3-丁二烯。用CYP诱导剂丙酮处理小鼠和大鼠的肝微粒体显示，VCH-1，2-环氧化物的形成增加了2倍。然而，与野生型小鼠相比，与来自CYP2E1缺陷小鼠的微生物体孵育相比，VCH的生物激活率与单环氧化物的生物活性没有差异。由于VCH诱导的卵毒性需要反复暴露于VCH，因此给大鼠灌服VCH 5或10d，以观察其对肝脏中细胞色素P450_2E_1浓度和/或相关活性的影响。免疫印迹分析和对硝基苯酚羟化实验表明，VCH预处理不能提高两种藻细胞中的细胞色素P450 2E 1的浓度或活性。根据这些数据，得出结论：在反复暴露于VCH后，在VCH的生物激活中，CYP2E1在小鼠和大鼠之间的物种差异中没有发挥作用。其他异构体，如CYP2A和CYP2B亚家族中的那些，可能参与VCH的生物激活。
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 B6C3F1mice 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 10d 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.