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.

Base-Displaced Intercalated Structure of the Food Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the Recognition Sequence of the NarI Restriction Enzyme, a Hotspot for −2 bp Deletions

“…There was no stacking between IQ and C 6 or C 8 . The observed NOEs (Table S4 in the Supporting Information) were consistent with the IQ H4A and H5A protons being directed toward C 18 and G 19 in the complementary strand, and the IQ H7A, H8A, and H9A protons being directed toward G 17 and C 18 in the complementary strand (Figure 10). The IQ methyl protons were closer to G 19 than to C 8 (Figure 10), also consistent with the observed NOEs (Table S4).…”

“…The downfield 31 P chemical shift at P 6 presumably reflects conformational perturbations associated with the P 6 phosphodiester. 84 The small differences observed for 31 P chemical shifts for P 17 and P 18 suggested that the phosphodiesters opposite to X 7 in the complementary strand were less perturbed. The carcinogen-base linkage site at X 7 residue is defined by the torsion angles α′…”

“…The G 17 imino proton was shielded by the IQ ring. However, the calculations suggested that the IQ ring tilted with respect to the DNA base pairs, presumably reducing stacking with base pairs C 6 ·G 19 and C 8 ·G 17 . This might be attributed to steric hindrance from the IQ methyl group.…”

“…The primary interaction involved base pair C 8 ·G 17 , the 3′-neighboring base pair with respect to X 7 . The G 17 imino proton was shielded by the IQ ring.…”

Smoking induced pancreatitis and pancreatic cancer

“…Approximately 46% of NNN and 26%-37% of NNK in tobacco is preformed and the remainder is pyrosynthesized from nicotine during smoking (36). Other harmful constituents of tobacco smoke include polycyclic aromatic hydrocarbons (PAHs), although their role in pancreatic disease remains unclear (7,36). In the following sections we will report the general effects of tobacco on the pancreas and subsequently focus on nicotine and NNK, since they are the most studied with respect to pancreatic disease.…”