Metabolism of polycyclic aza-aromatic carcinogens catalyzed by four expressed human cytochromes P450.
The role of human cytochromes P4501A1, -1A2, -3A4, and -3A5 in the metabolism of the polycyclic aza-aromatic hydrocarbons 7-methylbenz(c)acridine and dibenz(aj)acridine was investigated. The regioselectivity of the reactions was determined, as well as the associated stereoselectivity in the production of dihydrodiol metabolites and K-region oxides. Metabolite distributions were also examined in the presence of the epoxide hydrolase inhibitor 1,1,1-trichloropropylene-2,3-oxide and the P450 modulator alpha-naphthoflavone. P4501A2 was most regioselective for the production of the proximate carcinogen; the 3,4-dihydrodiol of 7-methylbenz(c)acridine and P4503A4 showed the highest regioselectivity for K-region oxidation. In contrast, the analogous putative proximate carcinogen of dibenz(aj)acridine was formed with the highest relative abundance by P4503A4, while P4501A2 was most regioselective for K-region oxidation. For both compounds the proximate carcinogens possessed predominantly 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 P4501A2 which favored production of the S,S isomer. In contrast the K-region dihydrodiol of dibenz(aj)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-methylbenz(c)acridine, while P4501A1 produced the 5R,6S-oxide with low optical purity. For dibenz(aj)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 relation to the activation and detoxification of toxicants.
Roberts-Thomson
S J
SJ
Department of Pharmacy, University of Sydney, New South Wales, Australia.
McManus
M E
ME
Tukey
R H
RH
Gonzalez
F J
FJ
Holder
G M
GM
D000166:Acridines / Q000378:metabolism*; D000818:Animals; D001372:Aza Compounds / Q000378:metabolism*; D001483:Base Sequence; D002273:Carcinogens / Q000378:metabolism*; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011083:Polycyclic Compounds / Q000378:metabolism*; D013237:Stereoisomerism
D000166:Acridines; D001372:Aza Compounds; D002273:Carcinogens; D011083:Polycyclic Compounds; C022289:dibenzacridine; C031277:7-methylbenz(c)acridine; D003577:Cytochrome P-450 Enzyme System