Roles of individual human cytochrome P-450 enzymes in the bioactivation of benzo(a)pyrene, 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, and other dihydrodiol derivatives of polycyclic aromatic hydrocarbons.

摘要: Human liver microsomes oxidized 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene [B(a)P-7,8-diol] to products that yield DNA adduct formation and umu gene expression in the tester system Salmonella typhimurium TA1535/pSK1002. The response is correlated levels of microsomal cytochrome P-450NF (P-450NF) nifedipine oxidation different human samples used for activation, both (+)- (-)-enantiomers B(a)P-7,8-diol gave similar results these other assays. was inhibited by antibodies raised against P-450NF. 7,8-Benzoflavone stimulated B(a)P-7,8-diol-dependent observed with purified lung microsomes. Thus, appears be major enzyme involved activation possibly lung. Similar were obtained trans-9,10-dihydroxy-9,10-dihydrobenzo(b)fluoranthene trans-3,4-dihydroxy-3,4-dihydro-7,12-dimethylbenz(a)anthracene, compounds are known form highly tumorigenic diol-epoxides. product (+)-B(a)P-7,8-diol cis-syn isomer benzo(a)pyrene-7,8,9,10-tetraol[7 beta, 8 alpha, 9 10 beta-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene]. Studies on nature enzymes [from benzo(a)pyrene] indicate neither P-450NF, P-450PA, P-450j, P-450DB, nor P-450MP involved. correlation 7,8-diol phenacetin O-deethylation a set partial inhibition reaction 7,8-benzoflavone anti-rat P-450 beta NF-B suggest may P1-450, ortholog rat NF-B, which catalyzes its subsequent tissues polycyclic hydrocarbon-treated rats. differential effects inhibitors benzo(a)pyrene 3-hydroxylation, 4,5-epoxidation, 9,10-epoxidation catalyzed an enzyme(s) distinct from forms 7,8-epoxide. roles differ rodent orthologs paradigm bioactivation hydrocarbons; further, flavones appear have opposing diol further epoxidation