Cytochrome P450 species involved in the metabolism of quinoline

• Published in: Carcinogenesis (New York) 1996-09, Vol.17 (9), p.1989-1996
• Main Authors: Reign, Geraldine, McMahon, Hugh, Ishizaki, Masao, Ohara, Toshinari, Shimane, Kiyomi, Esumi, Yoshi, Green, Carol, Tyson, Charles, Ninomiya, Shin-ichi
• Format: Article
• Language: English
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; Biotransformation; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - metabolism; Chemical agents; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP2A6; Cytochrome P-450 Enzyme System - metabolism; Humans; Kinetics; Male; Medical sciences; Methylcholanthrene - pharmacology; Mice; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Mixed Function Oxygenases - metabolism; Molecular Structure; Quinolines - metabolism; Rats; Rats, Sprague-Dawley; Recombinant Proteins - metabolism; Substrate Specificity; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/17.9.1989

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.