Chou M W, Heflich R H, Fu P P
Carcinogenesis. 1986 Nov;7(11):1837-44. doi: 10.1093/carcin/7.11.1837.
1-,3- and 6-Nitrobenzo[a]pyrene (nitro-BaP), which are prototypes of nitro polycyclic aromatic hydrocarbons (nitro-PAHs) derived from a carcinogenic parent PAH, benzo[a]pyrene, are environmental contaminants and potent bacterial mutagens. In this study, the aerobic and hypoxic metabolism of 1-nitro-BaP by rat liver microsomes was studied. Aerobic metabolism of 1-nitro-BaP yielded 1-nitro-BaP trans-7,8- and 9,10-dihydrodiol, while metabolism under hypoxic conditions yielded 1-amino-BaP. The metabolites formed from aerobic metabolism of 1-nitro-BaP and 1-nitro-BaP trans-9,10-dihydrodiol by liver microsomes of untreated rats and rats pretreated with 3-methylcholanthrene and phenobarbital were quantified. Comparison of these results with those obtained with BaP and BaP trans-9,10-dihydrodiol indicates that nitro substitution at the 1-position of BaP markedly affects the regioselectivity of the P-450-containing enzymes. 1-Nitro-BaP and the three metabolites were potent mutagens in Salmonella typhimurium TA98, both in the absence and in the presence of an exogenous metabolic activation system (S9). The direct and S9-mediated mutagenicities of 1-nitro-BaP and the two dihydrodiols were decreased in the nitroreductase-deficient strain TA98NR, while TA98/1,8-DNP6, an O-acetylase-deficient strain, was less sensitive to the two dihydrodiols, both with and without S9, and 1-nitro-BaP with S9. 1-Amino-BaP was equally mutagenic in all three tester strains. These observations indicate that: the metabolism of 1-nitro-BaP involves several pathways leading to mutagenic activation; the major activation pathways of 1-nitro-BaP involve nitroreduction; nitroreduction followed by O-acetylation is the major activation pathway of 1-nitro-BaP trans-7,8- and 9,10-dihydrodiol; and 1-amino-BaP is a potent direct-acting mutagen.
1-、3-和6-硝基苯并[a]芘（硝基苯并[a]芘）是源自致癌母体多环芳烃苯并[a]芘的硝基多环芳烃（硝基-PAHs）的原型，它们是环境污染物和强效细菌诱变剂。在本研究中，对大鼠肝微粒体中1-硝基苯并[a]芘的需氧和缺氧代谢进行了研究。1-硝基苯并[a]芘的需氧代谢产生1-硝基苯并[a]芘反式-7,8-和9,10-二氢二醇，而缺氧条件下的代谢产生1-氨基苯并[a]芘。对未处理大鼠以及用3-甲基胆蒽和苯巴比妥预处理的大鼠的肝微粒体对1-硝基苯并[a]芘和1-硝基苯并[a]芘反式-9,10-二氢二醇进行需氧代谢所形成的代谢产物进行了定量。将这些结果与用苯并[a]芘和苯并[a]芘反式-9,10-二氢二醇获得的结果进行比较，表明苯并[a]芘1位上的硝基取代显著影响含P-450酶的区域选择性。1-硝基苯并[a]芘及其三种代谢产物在鼠伤寒沙门氏菌TA98中均为强效诱变剂，无论是否存在外源性代谢活化系统（S9）。在硝基还原酶缺陷菌株TA98NR中，1-硝基苯并[a]芘以及两种二氢二醇的直接诱变活性和S9介导的诱变活性均降低，而O-乙酰化酶缺陷菌株TA98/1,8-DNP6对两种二氢二醇（无论有无S9）以及对加S9的1-硝基苯并[a]芘均不太敏感。1-氨基苯并[a]芘在所有三种测试菌株中的诱变活性相同。这些观察结果表明：1-硝基苯并[a]芘的代谢涉及多种导致诱变活化的途径；1-硝基苯并[a]芘的主要活化途径涉及硝基还原；硝基还原后进行O-乙酰化是1-硝基苯并[a]芘反式-7,8-和9,10-二氢二醇的主要活化途径；并且1-氨基苯并[a]芘是一种强效直接作用诱变剂。
