The biochemical basis for the species difference in hepatic microsomal 4-vinylcyclohexene epoxidation between female mice and rats.
The biochemical basis for the species difference in hepatic microsomal 4-vinylcyclohexene epoxidation between female mice and rats.
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DOI：
10.1093/carcin/11.11.1951
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发表时间：
1990-11
期刊：
影响因子：
4.7
通讯作者：
B. J. Smith;I. Sipes;J. Stevens;J. Halpert
中科院分区：
文献类型：
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作者：
B. J. Smith;I. Sipes;J. Stevens;J. Halpert
小鼠而非大鼠易受4-乙烯基环己烯（VCH）诱导的卵巢毒性和致癌性影响。这部分是由于VCH对卵毒性VCH-1,2-环氧化物的肝微粒体生物激活率高出4至6倍。这种差异的生化基础在微粒体中通过酶诱导、氯霉素或特异性抑制抗体的酶抑制以及与标记类固醇羟化酶活性的相关性来研究，以将VCH环氧化与特定的细胞色素P450形式联系起来。氯霉素处理小鼠微粒体中睾酮6 β -和15 α -羟化酶活性和VCH环氧化活性降低，初步提示P450IIIA和P450IIA形式可能参与VCH代谢。地塞米松（P450IIIA诱导剂）使睾酮6 β -羟化酶和VCH环氧化酶活性升高，抗大鼠P450IIIA IgG抑制睾酮6 β -羟化酶（68%），但对VCH环氧化酶活性无抑制作用。后者的结果不支持小鼠P450IIIA形式参与VCH环氧化。然而，获得的结果表明，小鼠P450IIA形式参与了VCH的环氧化。在未经处理的雌性小鼠微粒体中，小鼠P45015 α (P450IIA3)抗体抑制了48%的VCH环氧化酶活性，其浓度抑制了86%的睾酮15 α羟化酶活性。雌性大鼠肝微粒体未检测到与小鼠P45015 α相关的免疫化学蛋白。雌性小鼠和大鼠的肝微粒体对VCH的环氧化作用在苯巴比妥处理后增加，而在未处理的两种动物的肝微粒体中抗大鼠p450iib1 IgG的抑制作用约为三分之一。此外，129/J雌性小鼠（缺乏P450IIB形式的组成性表达）的微粒体VCH环氧化酶和睾酮16 α -羟化酶活性低于B6C3F1小鼠（34%）。这些结果提示P450IIB形式部分参与VCH微粒体环氧化。因此，P450型IIA和IIB占了雌性小鼠肝脏中VCH生物激活的大部分，这部分解释了小鼠对VCH诱导的卵巢毒性和致癌性的易感性。
Mice but not rats are susceptible to 4-vinylcyclohexene (VCH)-induced ovarian toxicity and carcinogenicity. This is due in part to a 4- to 6-fold greater rate of hepatic microsomal bioactivation of VCH to the ovotoxicant VCH-1,2-epoxide. The biochemical basis for this difference was investigated in microsomes using enzyme induction, enzyme inhibition with chloramphenicol or specific inhibitory antibodies, and correlation with marker steroid hydroxylase activities to associate VCH epoxidation with particular cytochrome P450 forms. Testosterone 6 beta- and 15 alpha-hydroxylase activities and VCH epoxidation were decreased in microsomes from chloramphenicol-treated mice, initially suggesting the possible involvement of P450IIIA and P450IIA forms in VCH metabolism. Although both testosterone 6 beta-hydroxylase and VCH epoxidase activities were increased by dexamethasone treatment (P450IIIA inducer), anti-rat P450IIIA IgG inhibited testosterone 6 beta-hydroxylase (68%) but not VCH epoxidase activity. These latter results do not support the involvement of mouse P450IIIA forms in VCH epoxidation. However, results were obtained which indicated that mouse P450IIA forms are involved in VCH epoxidation. In microsomes from untreated female mice VCH epoxidase activity was inhibited 48% by antibodies to mouse P45015 alpha (P450IIA3) at a concentration that inhibited testosterone 15 alpha-hydroxylase activity by 86%. No protein immunochemically related to mouse P45015 alpha was detected in female rat hepatic microsomes. VCH epoxidation by hepatic microsomes was increased in female mice and rats by phenobarbital treatment and was inhibited by approximately one-third by anti-rat-P450IIB1 IgG in microsomes from untreated animals of both species. Furthermore, microsomal VCH epoxidase and testosterone 16 alpha-hydroxylase activities were lower (34%) in female 129/J mice (deficient in constitutive expression of P450IIB forms) than in B6C3F1 mice. These results suggested partial involvement of P450IIB forms in the microsomal epoxidation of VCH. Therefore, P450 forms IIA and IIB account for the majority of VCH bioactivation in female mouse liver, which explains in part the susceptibility of mice to VCH-induced ovarian toxicity and carcinogenicity.