Role of metabolism in toxicity of inhaled 1,3 butadiene

1，3-丁二烯是一种广泛用于制造合成橡胶和其他聚合物的化学品。它对小鼠和大鼠都是致癌的，可能是人类的致癌物。它在几个测试系统中具有遗传毒性和突变性，包括哺乳动物细胞培养和小鼠，以及职业暴露的人类。丁二烯环氧化物代谢物似乎是其致癌和致突变作用的原因。研究表明，谷胱甘肽-S-转移酶T1基因多态性缺陷的人可能对丁二烯的遗传毒性效应更敏感。这项建议的一个目标是评估丁二烯代谢在丁二烯对小鼠的遗传毒性中的作用。我们推测，增加氧化代谢和/或减少代谢与谷胱甘肽的结合将增加丁二烯对小鼠的毒性。第二个目标是研究核苷酸切除修复(NER)在丁二烯诱导的突变中的作用，使用NER缺陷的小鼠，假设NER缺陷将增加小鼠对DNA损伤和突变的易感性。第三个目标将是评估新陈代谢和DNA修复方面的修改将如何修改丁二烯诱导的突变谱，假设这些修改将改变特定类型突变的相对频率。该项目的特异性在于：1)测量小鼠吸入低剂量丁二烯后，淋巴细胞突变和肺DNA损伤的剂量-反应关系；2)确定细胞色素P450 2EL增加或降低对丁二烯的遗传毒性和代谢的影响；3)利用含有XPA和XPC基因敲除突变的小鼠，确定核苷酸切除修复在丁二烯遗传毒性中的作用；4)确定上述处理小鼠淋巴细胞HPRT基因座的突变谱。通过更好地描述代谢和DNA修复在丁二烯诱导的小鼠遗传毒性中的作用，我们预计我们将能够对代谢和DNA修复基因的高频多态变异在人类丁二烯暴露风险中的作用做出更有见地的解释。

1,3-Buitadiene is a widely used chemical in the manufacture of synthetic rubber and other polymers. It is carcinogenic in mice and rats and is a probable human carcinogen. It is genotoxic and mutagenic in several test systems including mammalian cell culture and mice as well as occupationally exposed humans. Butadiene epoxide metabolites appear responsible for its carcinogenic and mutagenic effects. Studies suggest that humans with a polymorphic deficiency of glutathione-S-transferase T1 may be more sensitive to the genotoxic effects of butadiene. One goal of this proposal is to evaluate the role of butadiene metabolism in the genotoxicity of butadiene in mice. We hypothesize that increased oxidative metabolism and/or diminished conjugation of metabolism with glutathione will increase the toxicity of butadiene in mice. A second goal is to examine the role of nucleotide excision repair (NER) in butadiene- induced mutagenesis using NER deficient mice, hypothesizing that defective NER will increase the susceptibility of mice to DNA damage and mutation. A third goal will be to evaluate how modifications in metabolism and DNA repair will modify the spectrum of mutations induced by butadiene, hypothesizing that these modifications will alter the relative frequencies of specific types of mutations. The specific of the project are to 1) to measure the dose-response in mice to mutations in lymphocytes and DNA damage in lungs after exposure to low, doses of inhaled butadiene; 2) to determine how increased cytochrome P450 2El or decreased glutathione levels effect the genotoxicity and metabolism of butadiene; 3) to determine the role of nucleotide excision repair in the genotoxicity of butadiene using mice containing knockout mutations of the XPA and XPC genes; and 4) determine the spectrum of mutations in the hprt locus in lymphocytes from mice treated as described above. By better characterizing the role of metabolism and DNA repair in its butadiene-induced genotoxicity in mice we anticipate that we will be able to make more informed interpretations of the roles of high frequency polymorphic variants of metabolizing and DNA repair genes in human risk from butadiene exposure.