Metabolism of benzo[a]pyrene: conversion of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to highly mutagenic 7,8-diol-9,10-epoxides.
Metabolism of benzo[a]pyrene: conversion of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to highly mutagenic 7,8-diol-9,10-epoxides.
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DOI：
10.1073/pnas.73.10.3381
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发表时间：
1976-10
影响因子：
11.1
通讯作者：
D. Thakker;H. Yagi;A. Y. Lu;W. Levin;A. Conney
中科院分区：
文献类型：
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作者：
D. Thakker;H. Yagi;A. Y. Lu;W. Levin;A. Conney
用高压液相色谱法分析了（+/-）-反式7，8-二羟基-7，8-二氢苯并[a]芘在大鼠肝微粒体和高纯度单加氧酶系统中的代谢产物。四种立体异构的7，8，9，10-四氢苯并[a]芘的四元醇，即7，8-二氢二醇的9，10-环氧化物的两种高度致突变立体异构体的已知溶剂分解产物，被鉴定为产物。所形成的两种高度不稳定的二醇环氧化物（7 β，8 α-二羟基-9 β，10 β-环氧基-7，8，9，10-四氢苯并[a]芘，二醇环氧化物1; 7 β，8 α-二羟基-9 α，10 α-环氧基-7，8，9，10-四氢苯并[a]芘，二醇环氧化物2）的比例为约1.7至0.4。二醇环氧化物在37度下对烷基化磷酸盐缓冲液（pH 7.4）具有足够的反应性。微粒体，特别是对照动物的微粒体，形成了大量的额外代谢物，似乎是酚类。与苯并[a]芘类似，在用苯巴比妥或3-甲基胆蒽预处理大鼠后，7，8-二氢二醇的代谢表现出类似的诱导作用。基于在存在或不存在环氧化物水合酶的情况下形成的四醇的比率，二醇环氧化物似乎都不是环氧化物水合酶的底物。鉴于苯并[a]芘7，8-氧化物和7，8-二氢二醇的已知致癌性以及立体异构二醇环氧化物的显著致突变性，这两种二醇环氧化物都有资格被视为苯并[a]芘的“最终致癌物”。
Metabolites of (+/-)-trans 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene formed by a rat liver microsomes and by a highly purified monoxygenase system were analyzed by high-pressure liquid chromatography. Four stereoisomeric tetraols of 7,8,9,10-tetrahydrobenzo[a]pyrene, known solvolysis products of the two highly mutagenic stereoisomers of the 9,10-epoxide of the 7,8-dihydrodiol, were identified as products. The ratio of the two highly unstable diol epoxides formed (7 beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, diol epoxide 1; 7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, diol epoxide 2) ranged from about 1.7 to 0.4. The diol epoxides are sufficiently reactive to alkylate phosphate buffer (pH 7.4) at 37 degrees. Microsomes, particularly those from control animals, formed a substantial amount of an additional metabolite that appears to be phenolic. In analogy to benzo[a]pyrene, the metabolism of the 7,8-dihydrodiol shows similar induction after pretreatment of rats with phenobarbital or 3-methylcholanthrene. Neither diol epoxide appears to be a substrate for epoxide hydrase based on the ratis of tetraols formed in the presence or absence of epoxide hydrase. In view of the known carcinogenicity of benzo[a]pyrene 7,8-oxide and 7,8-dihydrodiol and of the marked mutagenicity of the stereoisomeric diol epoxides, both of these diol epoxides qualify for consideration as "ultimate carcinogen(s)" of benzo[a]pyrene.