Metabolism of benzo(a)pyrene and benzo (a)pyrene derivatives to mutagenic products by highly purified hepatic microsomal enzymes.

摘要: A highly purified and reconstituted hepatic microsomal monooxygenase system, completely free of epoxide hydrase consisting cytochrome P-448 from 3-methylcholanthrene-treated rats, NADPH-cytochrome c reductase, phosphatidylcholine, NADPH, metabolizes benzo (a)pyrene to products mutagenic in strains TA 98 1538 Salmonella typhimurium. The formation metabolites is dependent on the presence (a)pyrene, partially phosphatidylcholine. Mutation frequency both linearly related amount time incubation. Highly P-450 phenobarbital-treated rats relatively poor catalyzing (a)pyrene. Addition 7.5 75 units P-448-dependent system decreases number mutations by approximately 50% and30% 98, respectively. Additional amounts (300 units) fail further suppress mutations, indicating that at least some, but probably not all, are arene oxides. In absence a induced 4,5-oxide readily quenched hydrase, whereas diol metabolite [(+/-)-7 beta, 8alpha-dihydroxy-9beta, 10beta-epoxy-7,8,9,10-tetrahydrobenzo (a)pyrene] not. Several known potential phenolic dihydrodiol metabolized Salmonella. per nmol hemoprotein 3- 4-fold higher when trans-7,8-dihydroxy-7,8-dihydrobenzo replaces as substrate for system. Little or no activity observed with trans-dihydrodiols positions 4,5, 9,10, 11,12 hydrocarbon, either active Of 12 possible isomeric monophenols (a)-pyrene, only 6- 12-hydroxybenzo moderately bacterial mutagens; 1-, 2-, 3-, 6-, 9-, premutagens (i.e. products); 4-, 5-, 7-, 8-, 10-, 11-hydroxybenzo have little without oxidative metabolism. Benzo 7,8-oxide, carcinogen mouse skin, weakly can be mutagen(s), presumably epoxide(s), combination This first example direct role metabolic activation chemical toxic product.