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首页> 外文期刊>Mutation Research - Genetic Toxicology and Environmental Mutagenesis >Dioxin suppresses benzo[a]pyrene-induced mutations and DNA adduct formation through cytochrome P450 1A1 induction and (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide inactivation in human hepatoma cells
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Dioxin suppresses benzo[a]pyrene-induced mutations and DNA adduct formation through cytochrome P450 1A1 induction and (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide inactivation in human hepatoma cells

机译：二恶英通过细胞色素P450 1A1诱导和人肝癌细胞中的（±）-抗-苯并[a] py-7,8-二醇-9,10-环氧失活来抑制苯并[a] re诱导的突变和DNA加合物的形成

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Benzo[. a]pyrene (BaP) is metabolically activated by cytochrome P450 enzymes, and forms DNA adduct leading to mutations. Cytochrome P450 1A1 plays a central role in this activation step, and this enzyme is strongly induced by chemical agents that bind to the aryl hydrocarbon receptor (AhR), which is also known as a dioxin receptor. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand has not been shown to form any DNA adduct, but has a possibility to aggravate the toxicity of precarcinogenic polycyclic hydrocarbons through the induction of metabolic enzymes. We treated human hepatoma cells (HepG2) with TCDD, and subsequently exposed them to BaP to elucidate the synergistic effects on mutations. Surprisingly, mutant frequency induced by BaP at the hypoxanthine-guanine phosphribosyltransferase (HPRT) locus was decreased by pretreatment with TCDD. In correlation with decrease in the mutant frequencies, BaP-DNA adduct formation was also decreased by TCDD pretreatment. This suppressive effect of TCDD was more potent when the cells were exposed to (±)-anti-benzo[. a]pyrene-7,8-diol-9,10-epoxide (BPDE), a reactive metabolic intermediate of BaP. Among the enzymes catalyzing BaP oxidation and conjugation, cytochrome P450 1A1, 1A2, 3A4 and UDP-glucuronosyltransferase 1A1 mRNAs were induced by the exposure to TCDD. In cytochrome P450 1A1-deficient murine cells and cytochrome P450 1A1-uninducible human cells, TCDD could not suppress BPDE-DNA adduct formation. Further experiments using " Tet-On" cytochrome P450 1A1-overexpressing cells and a recombinant cytochrome P450 1A1 enzyme demonstrated that this is the key enzyme involved in the biotransformation of BaP, that is, both production and inactivation of BPDE. We conclude that TCDD-induced cytochrome P450 catalyzes the metabolism of BPDE to as yet-unidentified products that are not apparently DNA-reactive, thereby reducing mutations in hepatoma cells.
机译：苯并[。 py（BaP）被细胞色素P450酶代谢激活，并形成导致突变的DNA加合物。细胞色素P450 1A1在此激活步骤中起着关键作用，该酶由与芳烃受体（AhR）（也称为二恶英受体）结合的化学试剂强烈诱导。 2,3,7,8-四氯二苯并-对-二恶英（TCDD）（一种强力的AhR配体）尚未显示出可形成任何DNA加合物，但有可能通过诱导代谢酶来加剧前致癌性多环烃的毒性。我们用TCDD处理人肝癌细胞（HepG2），然后将其暴露于BaP以阐明对突变的协同作用。出人意料的是，通过用TCDD预处理，BaP在次黄嘌呤-鸟嘌呤磷酸核糖基转移酶（HPRT）基因座上诱导的突变体频率降低了。与突变体频率的减少相关，TCDD预处理也减少了BaP-DNA加合物的形成。当细胞暴露于（±）-抗-苯并[]时，TCDD的这种抑制作用更为有效。 a] py-7,8-二醇-9,10-环氧化物（BPDE），BaP的一种反应性代谢中间体。在催化BaP氧化和结合的酶中，暴露于TCDD可诱导细胞色素P450 1A1、1A2、3A4和UDP-葡萄糖醛酸转移酶1A1 mRNA的表达。在缺乏细胞色素P450 1A1的鼠类细胞和细胞色素P450 1A1不可诱导的人细胞中，TCDD不能抑制BPDE-DNA加合物的形成。使用“ Tet-On”细胞色素P450 1A1过表达细胞和重组细胞色素P450 1A1酶的进一步实验表明，这是参与BaP生物转化（即BPDE产生和失活）的关键酶。我们得出的结论是，TCDD诱导的细胞色素P450催化BPDE代谢为尚未识别的，显然不具有DNA反应性的产物，从而减少了肝癌细胞的突变。

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