大鼠肝脏微粒体和纯化的P4501A1对3,5,3',5'-四氯联苯的代谢

Metabolism of 3,5,3',5'-tetrachlorobiphenyl by rat liver microsomes and purified P4501A1.

Koga N, Nishimura N, Kuroki H, Masuda Y, Yoshimura H

Department of Food and Nutrition, Nakamura Gakuen University, Fukuoka, Japan.

Xenobiotica. 1994 Aug;24(8):775-83. doi: 10.3109/00498259409043277.

Abstract

The metabolism of 3,5,3',5'-tetrachlorobiphenyl (TCB) was investigated with liver microsomes and purified P450 from the male Wistar rat. 2. One novel metabolite was produced after incubation with liver microsomes derived from the 3-methylcholanthrene (MC)- and 3,4,5,3',4'-pentachlorobiphenyl-pretreated rat, but not after incubation with those from the untreated or phenobarbital (PB)-pretreated rat. These results suggest that P450 isozyme(s) induced by MC-type inducers is involved in 3,5,3',5'-TCB metabolism. 3. The chemical structure of this metabolite was identified to be 4-hydroxy-3,5,3',5'-TCB by comparison of its retention time in glc and the ms with those of a synthetic sample. 4. Purified rat P4501A1, a major MC-inducible P450 isozyme, catalyzed the 4-hydroxylation of 3,5,3',5'-TCB, but P4502B1, a major PB-inducible isozyme, was inactive. 5. Reduced glutathione completely inhibited the formation of the hydroxylated metabolite, suggesting that 4-hydroxylation of 3,5,3',5'-TCB proceeded via the 3,4-epoxide.

摘要

利用雄性Wistar大鼠的肝微粒体和纯化的细胞色素P450对3,5,3',5'-四氯联苯（TCB）的代谢进行了研究。2. 与来自经3-甲基胆蒽（MC）和3,4,5,3',4'-五氯联苯预处理大鼠的肝微粒体孵育后产生了一种新的代谢物，但与来自未处理或经苯巴比妥（PB）预处理大鼠的肝微粒体孵育后未产生。这些结果表明，由MC型诱导剂诱导的细胞色素P450同工酶参与了3,5,3',5'-TCB的代谢。3. 通过比较其在气相色谱中的保留时间和质谱与合成样品的保留时间和质谱，确定该代谢物的化学结构为4-羟基-3,5,3',5'-TCB。4. 纯化的大鼠细胞色素P4501A1是一种主要的MC诱导型细胞色素P450同工酶，催化了3,5,3',5'-TCB的4-羟基化反应，但主要的PB诱导型同工酶细胞色素P4502B1无活性。5. 还原型谷胱甘肽完全抑制了羟基化代谢物的形成，表明3,5,3',5'-TCB的4-羟基化反应是通过3,4-环氧化物进行的。