INVITRO ACTIVATION OF 1,2-DICHLOROETHANE BY MICROSOMAL AND CYTOSOLIC ENZYMES
INVITRO ACTIVATION OF 1,2-DICHLOROETHANE BY MICROSOMAL AND CYTOSOLIC ENZYMES
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DOI：
10.1016/0041-008x(80)90092-7
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发表时间：
1980-01-01
影响因子：
3.8
通讯作者：
WATANABE, PG
中科院分区：
文献类型：
--
作者：
GUENGERICH, FP;CRAWFORD, WM;WATANABE, PG
[1，2-14C]1，2-二氯乙烷[一种致癌工业化学品]被大鼠肝脏酶系统代谢成非挥发性产物以及与蛋白质和小牛胸腺DNA不可逆结合的产物。对所有3种代谢物的胞液代谢依赖于还原型谷胱甘肽(GSH)的存在，这表明GSH转移酶的作用。微粒体对3种产物的代谢都是通过混合功能氧化进行的，微粒体谷胱甘肽转移酶(S)催化与脱氧核糖核酸不可逆结合的代谢物的形成。GSH以协同方式抑制微粒体混合功能氧化酶(MFO)催化的与蛋白质的结合，但促进与DNA的结合。2-氯乙醛、S-(2-氯乙基)-谷胱甘肽和1-氯-2-氯乙烷是参与不可逆结合的主要物种，而氯乙烯、2-氯乙醇和氯乙基则不是。微粒体MFO、协同微粒体MFO-GSH转移酶和细胞质GSH转移酶系统对标记从二氯乙烷到各种同源核苷酸的不可逆结合的偏好不同，只有后者产生了对鼠伤寒沙门氏菌TA 1535具有诱变作用的代谢物。几条1，2-二氯乙烷活化途径是可行的，它们产生不同的加合物；估算了在这些体外检测条件下，每条途径对总非挥发性代谢物、致突变代谢物以及DNA和蛋白质加合物的相对贡献。
[1,2-14C]1,2-Dichloroethane [a tumorigenic industrial chemical] was metabolized by rat liver enzyme systems to nonvolatile products and to products irreversibly bound to protein and calf thymus DNA. Cytosolic metabolism to all 3 types of metabolites was dependent upon the presence of reduced glutathione (GSH), suggesting the role of GSH transferases. Microsomal metabolism to all 3 types of products occurred via mixed function oxidation; microsomal GSH transferase(s) catalyzed the formation of metabolites irreversibly bound to DNA. GSH blocked microsomal mixed function oxidase (MFO)-catalyzed binding to protein but stimulated binding to DNA in a synergistic manner. 2-Chloroacetaldehyde, S-(2-chloroethyl)-GSH and 1-chloroso-2-chloroethane are proposed as major species involved in irreversible binding but vinyl chloride, 2-chloroethanol and chloroethyl radicals are not. The microsomal MFO, synergistic microsomal MFO-GSH transferase and cytsolic GSH transferase systems differed in their preferences for irreversible binding of label from dichloroethane to various homopolyribonucleotides and only the latter system produced metabolites mutagenic to Salmonella typhimurium TA 1535. Several 1,2-dichloroethane activation pathways are operative which produce different adducts; the relative contribution of each pathway to total nonvolatile metabolites, mutagenic metabolites and DNA and protein adducts under these in vitro assay conditions was estimated.