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Relationship between Content and Activity of Cytochrome P450 and Induction of Heterocyclic Amine DNA Adducts in Human Liver Samples In vivo and In vitro

Laboratory for Analytical Toxicology, Department of Biosciences, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden

Requests for reprints: Lennart Moöller, Karolinska Institute, CNT, Novum, S-141 57 Huddinge, Sweden. Phone: 46-8-608-92-20; Fax: 46-8-774-68-33. E-mail: lennart.moller{at}cnt.ki.se

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 (AC), 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)-AC (3',5'-pdGp-C8-AC). 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 AC 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-AC 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-AC 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-AC 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.

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