METABOLISM OF POLYCYCLIC AZA-AROMATIC CARCINOGENS CATALYZED BY 4 EXPRESSED HUMAN CYTOCHROMES-P450

The role of human cytochromes P4501A1, -1A2, -3A4, and -3A5 in the met abolism of the polycyclic aza-aromatic hydrocarbons 7-methylbenz(c)acr idine and dibenz(a,j)acridine was investigated. The regioselectivity o f the reactions was determined, as well as the associated stereoselect ivity in the production of dihydrodiol metabolites and K-region oxides . Metabolite distributions were also examined in the presence of the e poxide hydrolase inhibitor 1,1,1-trichloropropylene-2,3-oxide and the P450 modulator Lu-naphthoflavone. P4501A2 was most regioselective for the production of the proximate carcinogen; the 3,4-dihydrodiol of 7-m ethylbenz(c)acridine and P4503A4 showed the highest regioselectivity f or K-region oxidation. In contrast, the analogous putative proximate c arcinogen of dibenz(a,j)acridine was formed with the highest relative abundance by P4503A4, while P4501A2 was most regioselective for K-regi on oxidation. For both compounds the proximate carcinogens possessed p redominantly the 3R,4R-absolute configuration, independent of the P450 catalyzing the reaction. The K-region dihydrodiols of 7-methylbenz (c )acridine were formed with no stereoselectivity, except with P1501A2 w hich favored production of the S,S isomer. In contrast the K-region di hydrodiol of dibenz(n,j)acridine was formed by P4501A1 and P4501A2 as the R,R isomer with almost 100% optical purity. P4501A2 and 3A4 showed no stereoselectivity in the formation of the K-region oxide of 7-meth ylbenz(c)acridine, while P4501A1 produced the 5R,6S-oxide with low opt ical purity. For dibenz(a,j)acridine 5,6-oxide, P4501A1 predominantly formed 5S,6R-oxide (80% pure). These results emphasize the importance of the composition and levels of expressed P450s of an individual in r elation to the activation and detoxification of toxicants.