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首页> 美国卫生研究院文献>other >Cytotoxicity genotoxicity and mutagenicity of 1-chloro-2-hydroxy-3-butene and 1-chloro-3-buten-2-one two alternative metabolites of 13-butadiene
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Cytotoxicity genotoxicity and mutagenicity of 1-chloro-2-hydroxy-3-butene and 1-chloro-3-buten-2-one two alternative metabolites of 13-butadiene

机译：1-氯-2-羟基-3-丁烯和1-氯-3-丁烯-2-一（13-丁二烯的两种替代代谢产物）的细胞毒性遗传毒性和致突变性

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The cytotoxicity, genotoxicity, and mutagenicity of 1-chloro-2-hydroxy-3-butene (CHB), a known in vitro metabolite of the human carcinogen 1,3-butadiene, have not previously been investigated. Because CHB can be bioactivated by alcohol dehydrogenases to yield 1-chloro-3-buten-2-one (CBO), a bifunctional alkylating agent that caused globin-chain cross-links in erythrocytes, in the present study we investigated the cytotoxic and genotoxic potential of CHB and CBO in human normal hepatocyte L02 cells using the MTT assay, the relative cloning efficiency assay and the comet assay. We also investigated the mutagenic potential of these compounds with the Ames test using Salmonella strains TA1535 and TA1537. The results provide clear evidence for CHB and CBO being both cytotoxic and genotoxic with CBO being approximately 100-fold more potent than CHB. Interestingly, CHB generated both single-strand breaks and alkali-labile sites on DNA, whereas CBO produced only alkali-labile sites. CHB did not directly result in DNA breaks, whereas CBO was capable of directly generating breaks on DNA. Interestingly, both compounds did not induce DNA cross-links as examined by the comet assay. The Ames test results showed that CHB induced point mutation but not frameshift mutation, whereas the toxic effects of CBO made it difficult to reliably assess the mutagenic potential of CBO in the two strains. Collectively, the results suggest that CHB and CBO may play a role in the mutagenicity and carcinogenicity of 1,3-butadiene.
机译：1-氯-2-羟基-3-丁烯（CHB）（一种人类致癌物1,3-丁二烯的已知体外代谢产物）的细胞毒性，遗传毒性和致突变性尚未得到研究。由于CHB可以被乙醇脱氢酶生物激活以产生1-氯-3-丁烯-2-一（CBO），一种双功能烷基化剂，可引起红细胞中的球蛋白链交联，因此在本研究中，我们研究了细胞毒性和基因毒性MTT法，相对克隆效率法和彗星法检测人正常肝细胞L02细胞中CHB和CBO的潜力我们还通过沙门氏菌菌株TA1535和TA1537的Ames试验研究了这些化合物的诱变潜力。结果提供了明确的证据，证明CHB和CBO具有细胞毒性和基因毒性，其中CBO的效力比CHB高约100倍。有趣的是，CHB在DNA上同时产生单链断裂和碱不稳定位点，而CBO仅产生碱不稳定位点。 CHB不会直接导致DNA断裂，而CBO能够直接在DNA上产生断裂。有趣的是，这两种化合物均未诱导彗星试验检测到的DNA交联。 Ames测试结果表明，CHB诱导了点突变，但没有移码突变，而CBO的毒性作用使得难以可靠地评估这两种菌株中CBO的诱变潜力。总体而言，结果表明CHB和CBO可能在1,3-丁二烯的致突变性和致癌性中起作用。

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