Carcinogenesis, Vol 18, 1085-1092, Copyright © 1997 by Oxford University Press
KE Anderson, GJ Hammons, FF Kadlubar, JD Potter, KR Kaderlik, KF Ilett, RF Minchin, CH Teitel, HC Chou, MV Martin, FP Guengerich, GW Barone, NP Lang and LA Peterson
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.
ARTICLES
Metabolic activation of aromatic amines by human pancreas
Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis 55454, USA.
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