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.

• DOI: 10.1073/pnas.86.20.7696
• Publication Date: 2006-05-31T11:05:49Z
• Authors: M A Butler; M Iwasaki; F P Guengerich; F F Kadlubar
• Keywords: Phenacetin; Demethylation

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