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。它对小鼠和大鼠具有致癌性，也是可能的人类致癌物。在包括哺乳动物细胞培养和小鼠以及职业暴露的人类在内的几个测试系统中，它具有遗传毒性和诱变性。环氧丁二烯代谢物似乎对其致癌和致突变作用负责。研究表明，具有谷胱甘肽- s -转移酶T1多态性缺乏症的人可能对丁二烯的遗传毒性作用更敏感。本研究的目的之一是评估丁二烯代谢在小鼠丁二烯遗传毒性中的作用。我们假设氧化代谢的增加和谷胱甘肽代谢结合的减少会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缺陷小鼠，假设NER缺陷会增加小鼠对DNA损伤和突变的易感性。第三个目标将是评估代谢和DNA修复中的修饰如何改变丁二烯诱导的突变谱，假设这些修饰将改变特定类型突变的相对频率。该项目的具体内容是：1)测量暴露于低剂量吸入丁二烯后小鼠淋巴细胞突变和肺部DNA损伤的剂量反应；2)测定细胞色素P450 2El升高和谷胱甘肽水平降低对丁二烯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)测定上述处理小鼠淋巴细胞中HPRT位点的突变谱。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性变异在人类暴露丁二烯风险中的作用做出更明智的解释。

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.