Metabolic activation of aromatic amines by human pancreas

Epidemiologic studies have suggested that aromatic amines (andnitroaromatic hydrocarbons) may be carcinogenic for human pancreas.Pancreatic tissues from 29 organ donors (13 smokers, 16 non-smokers) wereexamined for their ability to metabolize aromatic amines and othercarcinogens. Microsomes showed no activity for cytochrome P450 (P450)1A2-dependent N-oxidation of 4-aminobiphenyl (ABP) or for the followingactivities (and associated P450s): aminopyrine N-demethylation andethylmorphine N-demethylation (P450 3A4); ethoxyresorufin O- deethylation(P450 1A1) and pentoxyresorufin O-dealkylation (P450 2B6); p-nitrophenolhydroxylation and N-nitrosodimethyl-amine N-demethylation (P450 2E1);lauric acid omega-hydroxylation (P450 4A1); and 4-(methylnitrosamino)-1-(3-pyridyl-1-butanol) (NNAL) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) alpha-oxidation (P4501A2, 2A6, 2D6). Antibodies were used to examine microsomal levels of P4501A2, 2A6, 2C8/9/18/19, 2E1, 2D6, and 3A3/4/5/7 and epoxide hydrolase.Immunoblots detected only epoxide hydrolase at low levels; P450 levels were<1% of liver. Microsomal benzidine/prostaglandin hydroperoxidationactivity was low. In pancreatic cytosols and microsomes, 4-nitrobiphenylreductase activities were present at levels comparable to human liver. TheO-acetyltransferase activity (AcCoA- dependent DNA-binding of[3H]N-hydroxy-ABP) of pancreatic cytosols was high, about twothirds thelevels measured in human colon. Cytosols showed high activity forN-acetylation of p-aminobenzoic acid, but not of sulfamethazine, indicatingthat acetyltransferase-1 (NAT1) is predominantly expressed in this tissue.Cytosolic sulfotransferase was detected at low levels. Using32P-post-labeling enhanced by butanol extraction, putative arylamine-DNAadducts were detected in most samples. Moreover, in eight of 29 DNAsamples, a major adduct was observed that was chromatographically identicalto the predominant ABP- DNA adduct, N-(deoxyguanosin-8-yl)-ABP. Theseresults are consistent with a hypothesis that aromatic amines andnitroaromatic hydrocarbons may be involved in the etiology of humanpancreatic cancer.