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PubMed1997

Mutagenicity of carcinogenic nitrosamines when activated by hamster and human pancreatic duct epithelial cells.

We have measured the ability of pancreatic duct epithelial cells (DEC) from Syrian hamsters and humans and CK cells, immortalized hamster DEC, to metabolize chemical carcinogens to species that were mutagenic in S. typhimurium TA98 and in V79 cells. The chemicals were N-nitrosobis(2-oxopropyl)amine (BOP), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The ability of ethanol (EtOH) to modify the metabolizing efficiency was also measured. When an S9 preparation from EtOH-treated CK cells was used to metabolize NNK the number of revertants was 271 +/- 73 compared with 17 +/- 2 when the S9 from control CK cells was used. When hamster DEC were used there was no increase in the mutation frequency for BOP in V79 cells (64 +/- 20 mutants/10(6) survivors per mumol) when EtOH-DEC were used. However, the mutation frequencies of NNK and PhIP rose when the EtOH-treated DEC were used from 62 +/- 31 to 198 +/- 28 mutants/10(6) survivors per mumol for NNK and from 94 +/- 25 to 166 +/- 25 mutants/10(6) survivors per mumol for PhIP. A similar result was obtained when human DEC were used, i.e. no change in BOP mutagenicity and a slight increase in PhIP mutagenicity, from 34 +/- 14 to 65 +/- 12 mutants/10(6) survivors per mumol. There were large increases in the mutagenicity of NNK with each of the three samples of human DEC that were used, from 75 +/- 0 to 213 +/- 38, 75 +/- 13 to 175 +/- 25 and 38 +/- 13 to 285 +/- 25 mutants/10(6) survivors per mumol. The EtOH treatment regimen that was used more closely mimicked chronic exposure at low concentrations in vivo. These data show that hamster DEC are capable of metabolizing NNK, which is carcinogenic in these cells in vivo. Furthermore, human DEC metabolized NNK as efficiently as hamster DEC.

Adolescent↗
PubMed1998

Chemopreventive potential of fumaric acid, N-acetylcysteine, N-(4-hydroxyphenyl) retinamide and beta-carotene for tobacco-nitrosamine-induced lung tumors in A/J mice.

Four agents, fumaric acid (FA), N-acetylcysteine (NAC), N-(4-hydroxyphenyl) retinamide (4-HPR) and beta-carotene (beta-CT), were evaluated for potential chemopreventive activity using the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor model in female A/J mice. The agents were evaluated in both 16-week and 52-week bioassays at two dose levels corresponding to 0.8 maximum tolerated dose (MTD) and 0.4 MTD administered throughout the bioassay either in the diet (FA, 160 and 80 mmol/kg diet; NAC, 160 and 80 mmol/kg diet; 4-HPR, 4 and 2 mmol/kg diet) or by subcutaneous injection twice a week (beta-CT, 32 and 16 mg/kg b.w.). Mice were treated with a single i.p. dose of 10 micromol NNK in saline 1 week after administration of test agent. Lung adenomas were evaluated in the 16-week bioassay, whereas both adenomas and adenocarcinomas of the lung were determined in the 52-week bioassay. Both bioassays showed that all four agents did not significantly inhibit the total tumor incidence and multiplicity of the lung. However, the incidence of adenocarcinomas was reduced (P < 0.01) at 52 weeks in NNK groups given either 0.8 MTD NAC or 0.8 MTD beta-CT compared with the NNK control group. The decreases in adenocarcinomas were accompanied by corresponding increases in adenomas in these treatment groups. Thus, this study showed that FA, NAC, 4-HPR and beta-CT did not inhibit the total tumor formation, however, at the higher doses both NAC and beta-CT significantly retarded the malignant progression in the lung of NNK-treated A/J mice.

Acetylcysteine↗
PubMed1991

Nitrosamine-induced cancer: O4-alkylthymine produces sites of DNA hyperflexibility.

The carcinogenic properties of N-nitroso compounds are associated with their ability to alkylate DNA, in particular to form O6-alkylguanine and O4-alkylthymine. DNA duplexes containing either O6-alkylguanine or O4-alkylthymine were synthesized, and each duplex was ligated to form a set of DNAs of increasing length with the alkylated base out of phase (16 base-pairs apart) or in phase (21 base-pairs apart) with the helical repeat of the DNA. The DNA contained the sequence 5' CAA 3', which is the 61st codon of the K-ras gene, because this codon is a preferred site of mutation for a number of carcinogens including the methylating carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK). O4-Methylthymine or O4-ethylthymine replaced thymine in either of the two A.T base-pairs of this codon (normally CAA), and O6-methylguanine replaced the guanine in the G.C pair. All the sequences containing O4-alkylthymine exhibited anomalous, slow, gel migration and ligated to form circles of unusually small diameter. In general, the effect was seen when the alkylated base-pair was out of phase with the helical repeat as well as when it was in phase, suggesting that the alkylated base-pair confers flexibility which is largely isotropic, i.e., has no preferred direction, rather than anisotropic flexibility or bending. However, at pH 8.3 the 21-base-pair set containing O4-alkylT.A had significantly greater anomalous migration than the 16-base-pair set, suggesting that the flexibility produced by this base-pair has a significant anisotropic component and thus resembles true bending.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗