Impact of metabolic genotypes on levels of biomarkers of genotoxic exposure

Phase I and Phase II xenobiotic-metabolising enzyme families are involved i n the metabolic activation and detoxification of various classes of environ mental carcinogens. Particular genetic polymorphisms of these enzymes have been shown to influence individual cancer risk. A brief overview is present ed about recent research of the relationship between metabolic genotypes an d internal dose, biologically effective dose and cytogenetic effects of com plex and specific genotoxic exposures of human study populations, and we re port our new results from two molecular epidemiological studies. We investi gated the effects of multiple interactions among CYP1A1 Ile462Val CYP1A1 Ms pI, CYP1B1 Leu432Val, CYP2C9 Arg144Cys, CYP2C9 Ile359Leu, NQO1 Pro189Ser, G STM1 gene deletion and GSTP1 Ile105Val genotypes on the levels of carcinoge n-DNA adducts determined by P-32-postlabelling and PAH-DNA immunoassay in p eripheral blood lymphocytes from workers occupationally exposed to polycycl ic aromatic hydrocarbons in aluminium plants, and in bronchial tissue from smoking lung patients. A statistically significant positive linear correlat ion was observed between white blood cell aromatic DNA adduct and urinary 1 -hydroxypyrene (1-OHPY) levels from potroom workers with GSTM1 null genotyp e (P = 0.011). Our results suggest interactions between GSTM1 and GSTP1 all eles in modulation of urinary 1-OHPY levels and white blood cell DNA adduct levels in the PAH-exposed workers. Interactions between GSTM1 and GSTP1 al leles, in association with particular genotype combinations of CYPs, were a lso recognised in bronchial aromatic DNA adduct levels of smoking lung pati ents, The impact of single metabolic genotypes and their combinations on bi omarkers of exposure was usually weak, if any, in both our studies and repo rts of the literature. The effect of special metabolic gene interactions ma y be better recognised if the compared groups of individuals are stratified for multiple potential modulators of the observable biomarker end-point, a nd/or if chemical structure-specific biomarker methods are applied. (C) 200 1 Elsevier Science B.V. All rights reserved.