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© 1996 Oxford University Press

research-article

Cytochrome P450 species involved in the metabolism of quinoline

Geraldine Reign 1, Hugh McMahon, Masao Ishizaki, Toshinari Ohara, Kiyomi Shimane, Yoshi Esumi, Carol Green 2, Charles Tyson 2 and Shin-ichi Ninomiya

1Daiichi Pure Chemicals Co. Ltd 2117 Muramatsu, Tokai, Ibaraki 319-11, Japan
2SR1 International, 333 Ravenswood Avenue Menlo Park, CA 94025-3493, USA

1To whom correspondence should be addressed

Quinoline is a hepatocarcinogen in rats and mice and a well-known mutagen in bacteria after incubation with rat liver microsomes. The specific cytochrome P450 enzymes involved in quinoline metabolism in human and rat liver microsomes were determined using cDNA-expressed cytochrome P450s, correlations with specific cytochrome P450-linked monooxygenase activities in human liver microsomes and inhibition by specific inhibitors and antibodies. CYP2A6 is the principal cytochrome P450 involved in the formation of quinoline-1-oxide in human liver micro-somes (correlation coefficient r = 0.95), but is formed in only minute quantities in rat liver microsomes. CYP2E1 is the principal cytochrome P450 involved in the formation of 3-hydroxyquinoline (r = 0.93) in human liver microsomes and is involved in the formation in rat liver microsomes. A high correlation coefficient (r = 0.91) between CYP2A6 activity and quinoline-5,6-diol formation in human liver microsomes was observed, but this most likely reflects the involvement of CYP2A6 in the formation of quinoline-5,6-epoxide, from which the quinoline-5,6-diol is formed, as conversion of quinoline-5,6-epoxide to quinoline-5,6-diol on incubation of the epoxide with CYP2A6 could not be demonstrated. A cDNA-expressed human microsomal epoxide hydrolase, however, efficiently converted the epoxide to the diol and the microsomal epoxide inhibitor cyclohexene oxide inhibited quinoline-5,6-diol formation in rat liver microsomes. A preliminary kinetic analysis of quinoline metabolism in human liver microsomes was carried out and Eadie-Hofstee plots indicate that the formation of quinoline-5,6-diol is monophasic, while that of quinoline-1-oxide and 3-hydroxyquinoline is biphasic.


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