Octachlorostyrene induces cytochrome P450, UDP-glucuronosyltransferase, and sulfotransferase via the aryl hydrocarbon receptor and constitutive androstane receptor.
Octachlorostyrene induces cytochrome P450, UDP-glucuronosyltransferase, and sulfotransferase via the aryl hydrocarbon receptor and constitutive androstane receptor.
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DOI：
10.1093/toxsci/kfp130
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发表时间：
2009-09
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影响因子：
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通讯作者：
Y. Yanagiba;Yuki Ito;M. Kamijima;F. Gonzalez;T. Nakajima
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文献类型：
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作者：
Y. Yanagiba;Yuki Ito;M. Kamijima;F. Gonzalez;T. Nakajima
八氯苯乙烯（OCS）是氯化物合成过程中的副产物。有关接触网对环境的污染已有报道，但对人体的毒理学效应研究较少。药物代谢酶可能通过代谢活化或失活OCS在毒性中发挥重要作用。在这项研究中，我们调查了OCS是否影响这些酶使用野生型和芳香烃受体（Ahr）-null小鼠; AhR调节细胞色素P450（P450）1A，UDP-葡萄糖醛酸转移酶（UGT），或磺基转移酶（SULT）。通过管饲法用OCS（0、32和64 mumol/kg）处理两种小鼠品系4天。作为参考，用20 mg/kg 3-甲基胆蒽（3MC）处理小鼠4天。OCS处理仅在野生型小鼠中增加了CYP1A1和CYP1A2 mRNA的表达和乙氧基间苯二酚O-脱乙基酶活性，与AhR激活剂3MC相似。OCS处理仅在Ahr缺失小鼠中增加UGT 1A6和SULT 1A1 mRNA的表达及其相关酶活性，而3MC仅在野生型小鼠中仍然影响这些酶。OCS诱导的组成型雄烷受体（CAR），只有在Ahr-null小鼠，和靶基因CYP2B10 mRNA的诱导更强烈的Ahr-null小鼠比野生型小鼠。3MC仅在野生型小鼠中轻微诱导CYP2B10 mRNA。这些结果表明CAR参与OCS对UGT和SULT基因的调节。因此，OCS可能通过AhR调节CYP1A，而它通过CAR控制UGT1A6和SULT1A。
Octachlorostyrene (OCS) is a byproduct produced in the process of synthesis of chlorinated compounds. There are some reports concerning environmental contamination by OCS, but few on the toxicological effects on human. Drug-metabolizing enzymes may play an important role in toxicity through metabolic activation or deactivation of OCS. In this study, we investigated whether OCS influences these enzymes using wild-type and aryl hydrocarbon receptor (Ahr)-null mice; AhR regulates cytochrome P450 (CYP) 1A, UDP-glucuronosyltransferase (UGT), or sulfotransferase (SULT). Both mouse lines were treated with OCS (0, 32, and 64 mumol/kg) for 4 days by gavage. As a reference, the mice were treated with 20 mg/kg 3-methylcholanthrene (3MC) for 4 days. OCS treatment increased the expression of CYP 1A1 and CYP1A2 mRNA and ethoxyresorfin O-deethylase activity only in the wild-type mice, similar to that of the AhR activator 3MC. OCS treatment increased expression of UGT1A6 and SULT 1A1 mRNA and their associated enzyme activities only in Ahr-null mice, whereas 3MC still influenced these enzymes only in wild-type mice. OCS induced constitutive androstane receptor (CAR) only in Ahr-null mice, and the target gene CYP2B10 mRNA was induced more strongly in Ahr-null mice than in wild-type mice. 3MC slightly induced CYP2B10 mRNA only in the wild-type mice. These results suggest that CAR is involved in regulation of the UGT and SULT genes by OCS. Thus, OCS may regulate CYP1A via AhR, whereas it controls UGT1A6 and SULT1A via CAR.