Role of polymorphic CYP2E1 and CYP2D6 genes in NNK-induced chromosome aberrations in cultured human lymphocytes

Polymorphisms in genes of xenobiotic-metabolizing enzymes are largely respo nsible for interindividual differences in ability to activate and detoxify genotoxic agents and therefore may influence individual susceptibility to e nvironmental cancer. The tobacco-specific nitrosamine, 4-(methylnitrosamino )-1-(3-pyridyl)-1-butanone (NNK), requires metabolic activation by cytochro me P450 (CYP) enzymes to generate DNA-reactive intermediates that induce mu tations and cancer. In the current study, we investigated the role of the p olymorphic CYP2E1 and CYP2D6 genes in the genotoxicity of NNK( using the ta ndem-probe fluorescence in-situ hybridization (FISH) chromosome aberration assay as a marker. Our results, using whole blood cultures from 39 voluntee rs, indicated that NNK( (0.12, 0.24 or 0.72 mM) induced a concentration-dep endent increase in the frequency of chromosome aberration. The potential ro le of CYP2E1 and CYP2D6 in NNK-induced genetic damage in cultured human lym phocytes was characterized using specific CYP inhibitors. Treatment of bloo d cultures with 25 mu M diethyldithiocarbamate (DDC), a specific CYP2E1 inh ibitor, or 0.5 mu M quinidine, a specific CYP2D6 inhibitor, simultaneously with NNK(, significantly decreased NNK-induced chromosome aberration. We al so studied the role of CYP2E1 and CYP2D6 allelic variants on NNK-induced ch romosome aberration. Our results indicate that NNK induced a significantly higher level of chromosome aberration in cells with the CYP2E1 WT/*5B genot ype compared to cells with the CYP2E1 WT/WT. In contrast, no difference in NNK-induced chromosome aberration was observed between cells with the CYP2D 6 extensive metabolizers compared to cells with the CYP2D6 poor metabolizer genotypes. These results underscore the important role of polymorphic meta bolizing genes in influencing the genotoxic responses to environmental muta gens and provide support to the reported findings linking CYP2E1 polymorphi sm to smoking-related lung cancer. Pharmacogenetics 10:239-249 (C) 2000 Lip pincott Williams & Wilkins.