Affiliation:
1. Laboratory for Analytical Toxicology, Department of Biosciences, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden
Abstract
Abstract
This study was designed to estimate a correlation between metabolic activation phenotypes and formation of DNA adducts by heterocyclic amines (HCA) in 15 liver samples from healthy donors. The correlation between the amount of endogenous DNA adducts and the content of cytochrome P450 in human liver samples in vivo was statistically significant at r2 = 0.71 and P < 0.005. Furthermore, the isolated human liver microsomes were treated in vitro with two HCAs, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-9H-pyrido[2,3-b]indole (AαC), which have been recognized to induce two DNA adducts: 3′,5′-diphosphate-N-(2′-deoxyguanosin-8-yl)-PhIP (3′,5′-pdGp-C8-PhIP) and 3′,5′-diphosphate-N-(2′-deoxyguanosin-8-yl)-AαC (3′,5′-pdGp-C8-AαC). The correlations between the amount of DNA adducts induced by both compounds in vitro and the content of cytochrome P450 in human microsomes are statistically significant at r2 = 0.69 and r2 = 0.62 (P < 0.001), respectively. Furthermore, the level of DNA adducts after treatment with PhIP and AαC correlated with the activities of three isozymes of cytochrome P450: CYP1A1, CYP1A2, and CYP3A4. Therefore, three chemical inhibitors were used in the experiments: ellipticine against CYP1A1, furafylline against CYP1A2, and troleandomycin against CYP3A4. The highest inhibition levels in the formation of 3′,5′-pdGp-C8-PhIP and 3′,5′-pdGp-C8-AαC adducts were estimated to occur in the presence of furafylline at 56% and 69%, respectively. Ellipticine was involved in the inhibition of 40% of 3′,5′-pdG-C8-PhIP adducts and in only 18% of the inhibition of 3′,5′-pdGp-C8-AαC adducts. Troleandomycin did not significantly inhibit the formation of 3′,5′-pdGp-C8-PhIP adducts under these conditions, but it inhibited the formation of 31% of the 3′,5′-pdGpC8-AαC adducts. We conclude that the formation of DNA adducts can be used as a relevant marker of interindividual variability in the metabolic activation of HCAs in humans.
Publisher
American Association for Cancer Research (AACR)
Reference23 articles.
1. Lang NP, Butler MA, Massengill J, et al. Rapid metabolic phenotypes for acetyltransferase and cytochrome P4501A2 and putative exposure to food-borne heterocyclic amines increase the risk for colorectal cancer or polyps. Cancer Epidemiol Biomarkers & Prev 1994;3:675-82.
2. Johansson MAE, Jägerstad M. Occurrence of mutagenic/carcinogenic heterocyclic amines in meat and fish products, including pan residues, prepared under domestic conditions. Carcinogenesis 1994;15:1511-18.
3. Felton JS, Jagerstad M, Knize MG, Skog K, Wakabayashi K. Contents in foods, beverages and tobacco. In: Nagao M, Sugimura T, editors. Food borne carcinogens heterocyclic amine. West Sussex: John Wiley & Sons Ltd.; 2000. p. 31-71.
4. Friesen MD, Kaderlik K, Lin D, et al. Analysis of DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in rat and human tissues by alkaline hydrolysis and gas chromatography/electron capture mass spectrometry: validation by comparison with 32P-postlabeling. Chem Res Toxicol 1994;7:733-39.
5. Totsuka Y, Fukutome K, Takahashi M, et al. Presence of N2-(deoxyguanosin-8-yl)-2-amino-3,8-dimethylimidazo[4,5-f]quino-xaline (dG-C8-MeIQx) in human tissues. Carcinogenesis 1996;17:1029-34.
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