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Human Liver Microsomal Cytochrome P-450 Enzymes Involved in the Bioactivation of Procarcinogens Detected by umu Gene Response in Salmonella typhimurium TA 1535/pSK1002¹

Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

A total of 57 procarcinogens was examined for induction of umu gene response in the chimeric plasmid pSK1002, carried in Salmonella typhimurium TA 1535, after incubation with a series of human liver microsomal preparations which had been selected on the basis of characteristic levels of individual cytochrome P-450 (P-450) enzymes. The 18 most active compounds were selected and further analyzed using the umu gene response and correlative studies with a larger number of microsomal preparations, enzyme reconstitution studies involving purified enzymes, immunochemical inhibition, and patterns of stimulation and inhibition of catalytic activity by 7,8-benzoflavone. The results collectively indicate that 16 of these 18 most potent genotoxins examined are activated primarily either by P-450_NF (the nifedipine oxidase) or P-450_PA (the phenacetin O-deethylase). P-450_NF appears to be the major enzyme involved in the bioactivation of aflatoxin B₁, aflatoxin G₁, sterigmatocystin, trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, 6-aminochrysene, and tris-(2,3-dibromopropyl)phosphate in human liver. P-450_PA appears to be the major enzyme involved in the bioactivation of 2-amino-3-methylimidazo[4,5-f]quinoline, 2-amino-3,5-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-aminoanthracene, 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole, 2-aminofluorene, 2-acetylaminofluorene, 4-aminobiphenyl, 3-amino-1-methyl-5H-pyrido[4,3-b]indole, and 2-aminodipyrido[1,2-a:3',2'-d]imidazole. More than one enzyme appears to contribute significantly to the bioactivation of the other two compounds examined, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole and 6-nitrochrysene. The literature suggests that the two human liver P-450s involved in activation of these 16 procarcinogens are highly inducible by barbiturates, macrolide antibodies, and certain steroids (P-450_NF) and by smoking and ingestion of charcoal-containing food (P-450_PA); noninvasive assays are available to monitor the function of both P-450_NF and P-450_PA.

¹ Supported in part by USPHS Grants CA 44353 and ES 00267.

² Present address: Osaka Prefectural Institute of Public Health, Nakamichi, Higashinari-ku, Osaka 537, Japan.

³ Burroughs Wellcome Scholar in Toxicology (1983–1988). To whom requests for reprints should be addressed.

Received 11/ 1/88. Revised 3/20/89. Accepted 3/22/89.

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