Roles of human hepatic and pulmonary cytochrome P450 enzymes in the metabolism of the environmental carcinogen 6-nitrochrysene.
6-Nitrochrysene is remarkably tumorigenic in the lung and liver of newborn mice and approximates the activities of certain ultimate carcinogenic metabolites of polycyclic aromatic hydrocarbons. Previous studies have indicated that the major metabolic activation pathway of 6-nitrochrysene in newborn mice is initially through the formation of the proximate tumorigen trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysene with subsequent formation of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-aminochrysene. In order to provide information on the possible risk associated with human exposure to 6-nitrochrysene, the ability of human hepatic and pulmonary microsomes to metabolize 6-nitrochrysene was investigated. The major metabolites identified in 11 hepatic microsomes were trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene, trans-9,10-dihydro-9,10-dihydroxy-6-nitrochrysene, trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysene, 6-aminochrysene, and chrysene-5,6-quinone. Following the incubations of 6-nitrochrysene with 11 different human pulmonary microsomes, qualitatively similar metabolic patterns were obtained, although quantitative differences were evident. These results demonstrated that human liver and lung are capable of metabolizing 6-nitrochrysene to known potent carcinogenic metabolites via ring oxidation and nitroreduction. In an attempt to define the roles of individual human hepatic P450 involved in the metabolism of 6-nitrochrysene, the catalytic activities known to be associated with a specific P450 were analyzed and compared with the levels of each metabolite of 6-nitrochrysene formed with the same microsomes. Rates of phenacetin O-deethylation (P450 1A2) and nifedipine oxidation (P450 3A4) were well correlated with the rates of formation of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-aminochrysene, respectively. Inhibition studies with specific P450 inhibitors and antibodies further support the view that P450 1A2 and P450 3A4 are the major forms responsible for the formation of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-aminochrysene, respectively, in human liver. Further metabolism of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene appears to require P450 3A4. In the human lung, P450 1A1 appears to play a major role in the metabolism of 6-nitrochrysene to trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene. These results provide some requisite knowledge for evaluating human susceptibility to 6-nitrochrysene.
Chae
Y H
YH
Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595.
Yun
C H
CH
Guengerich
F P
FP
Kadlubar
F F
FF
el-Bayoumy
K
K
D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002911:Chrysenes / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000201:enzymology*; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology*
D002273:Carcinogens; D002911:Chrysenes; C035986:6-nitrochrysene; D003577:Cytochrome P-450 Enzyme System