title: Metabolic activation of aromatic amines by human pancreas.
abstract: Epidemiologic studies have suggested that aromatic amines (and nitroaromatic hydrocarbons) may be carcinogenic for human pancreas. Pancreatic tissues from 29 organ donors (13 smokers, 16 non-smokers) were examined for their ability to metabolize aromatic amines and other carcinogens. Microsomes showed no activity for cytochrome P450 (P450) 1A2-dependent N-oxidation of 4-aminobiphenyl (ABP) or for the following activities (and associated P450s): aminopyrine N-demethylation and ethylmorphine N-demethylation (P450 3A4); ethoxyresorufin O-deethylation (P450 1A1) and pentoxyresorufin O-dealkylation (P450 2B6); p-nitrophenol hydroxylation 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 (P450 1A2, 2A6, 2D6). Antibodies were used to examine microsomal levels of P450 1A2, 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 hydroperoxidation activity was low. In pancreatic cytosols and microsomes, 4-nitrobiphenyl reductase activities were present at levels comparable to human liver. The O-acetyltransferase activity (AcCoA-dependent DNA-binding of [3H]N-hydroxy-ABP) of pancreatic cytosols was high, about twothirds the levels measured in human colon. Cytosols showed high activity for N-acetylation of p-aminobenzoic acid, but not of sulfamethazine, indicating that acetyltransferase-1 (NAT1) is predominantly expressed in this tissue. Cytosolic sulfotransferase was detected at low levels. Using 32P-post-labeling enhanced by butanol extraction, putative arylamine-DNA adducts were detected in most samples. Moreover, in eight of 29 DNA samples, a major adduct was observed that was chromatographically identical to the predominant ABP-DNA adduct, N-(deoxyguanosin-8-yl)-ABP. These results are consistent with a hypothesis that aromatic amines and nitroaromatic hydrocarbons may be involved in the etiology of human pancreatic cancer.
authors.affiliation: Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis 55454, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Anderson
authors.forename: G J
authors.initials: GJ
authors.lastname: Hammons
authors.forename: F F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: J D
authors.initials: JD
authors.lastname: Potter
authors.forename: K R
authors.initials: KR
authors.lastname: Kaderlik
authors.forename: K F
authors.initials: KF
authors.lastname: Ilett
authors.forename: R F
authors.initials: RF
authors.lastname: Minchin
authors.forename: C H
authors.initials: CH
authors.lastname: Teitel
authors.forename: H C
authors.initials: HC
authors.lastname: Chou
authors.forename: M V
authors.initials: MV
authors.lastname: Martin
authors.forename: F P
authors.initials: FP
authors.lastname: Guengerich
authors.forename: G W
authors.initials: GW
authors.lastname: Barone
authors.forename: N P
authors.initials: NP
authors.lastname: Lang
authors.forename: L A
authors.initials: LA
authors.lastname: Peterson
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000588:Amines / Q000378:metabolism*; D001711:Biotransformation; D001713:Biphenyl Compounds / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008861:Microsomes / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism; D010084:Oxidation-Reduction; D010179:Pancreas / Q000378:metabolism*; D012907:Smoking
chemical_list: D000588:Amines; D001713:Biphenyl Compounds; D009602:Nitrosamines; D000123:Acetyltransferases; C099565:4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol; C040438:4-nitrobiphenyl