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Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines.

Butler M.A., Iwasaki M., Guengerich F.P., Kadlubar F.F.

Aromatic amines are well known as occupational carcinogens and are found in cooked foods, tobacco smoke, synthetic fuels, and agricultural chemicals. For the primary arylamines, metabolic N-oxidation by hepatic cytochromes P-450 is generally regarded as an initial activation step leading to carcinogenesis. The metabolic activation of 4-aminobiphenyl, 2-naphthylamine, and several heterocyclic amines has been shown recently to be catalyzed by rat cytochrome P-450ISF-G and by its human ortholog, cytochrome P-450PA. We now report that human hepatic microsomal caffeine 3-demethylation, the initial major step in caffeine biotransformation in humans, is selectively catalyzed by cytochrome P-450PA. Caffeine 3-demethylation was highly correlated with 4-aminobiphenyl N-oxidation (r = 0.99; P less than 0.0005) in hepatic microsomal preparations obtained from 22 human organ donors, and both activities were similarly decreased by the selective inhibitor, 7,8-benzoflavone. The rates of microsomal caffeine 3-demethylation, 4-aminobiphenyl N-oxidation, and phenacetin O-deethylation were also significantly correlated with each other and with the levels of immunoreactive human cytochrome P-450PA. Moreover, a rabbit polyclonal antibody raised to human cytochrome P-450PA was shown to inhibit strongly all three of these activities and to inhibit the N-oxidation of the carcinogen 2-naphthylamine and the heterocyclic amines, 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole and 2-amino-3-methylimidazo[4,5-f]-quinoline. Human liver cytochrome P-450PA was also shown to catalyze caffeine 3-demethylation, 4-aminobiphenyl N-oxidation, and phenacetin O-deethylation. Thus, estimation of caffeine 3-demethylation activity in humans may be useful in the characterization of arylamine N-oxidation phenotypes and in the assessment of whether or not the hepatic levels of cytochrome P-450PA, as affected by environmental or genetic factors, contribute to interindividual differences in susceptibility to arylamine-induced cancers.

Proc. Natl. Acad. Sci. U.S.A. 86:7696-7700(1989) [PubMed] [Europe PMC]