Impact of metabolic genotypes on levels of biomarkers of genotoxic exposure.
Phase I and Phase II xenobiotic-metabolising enzyme families are involved in the metabolic activation and detoxification of various classes of environmental carcinogens. Particular genetic polymorphisms of these enzymes have been shown to influence individual cancer risk. A brief overview is presented about recent research of the relationship between metabolic genotypes and internal dose, biologically effective dose and cytogenetic effects of complex and specific genotoxic exposures of human study populations, and we report our new results from two molecular epidemiological studies. We investigated the effects of multiple interactions among CYP1A1 Ile462Val, CYP1A1 MspI, CYP1B1 Leu432Val, CYP2C9 Arg144Cys, CYP2C9 Ile359Leu, NQO1 Pro189Ser, GSTM1 gene deletion and GSTP1 Ile105Val genotypes on the levels of carcinogen-DNA adducts determined by (32)P-postlabelling and PAH-DNA immunoassay in peripheral blood lymphocytes from workers occupationally exposed to polycyclic aromatic hydrocarbons in aluminium plants, and in bronchial tissue from smoking lung patients. A statistically significant positive linear correlation was observed between white blood cell aromatic DNA adduct and urinary 1-hydroxypyrene (1-OHPY) levels from potroom workers with GSTM1 null genotype (P=0.011). Our results suggest interactions between GSTM1 and GSTP1 alleles in modulation of urinary 1-OHPY levels and white blood cell DNA adduct levels in the PAH-exposed workers. Interactions between GSTM1 and GSTP1 alleles, in association with particular genotype combinations of CYPs, were also recognised in bronchial aromatic DNA adduct levels of smoking lung patients. The impact of single metabolic genotypes and their combinations on biomarkers of exposure was usually weak, if any, in both our studies and reports of the literature. The effect of special metabolic gene interactions may be better recognised if the compared groups of individuals are stratified for multiple potential modulators of the observable biomarker end-point, and/or if chemical structure-specific biomarker methods are applied.
Schoket
B
B
Department of Biochemistry, National Institute of Environmental Health, József Fodor National Centre for Public Health, Budapest H-1097, Hungary. schoket@oki1.joboki.hu
Papp
G
G
Lévay
K
K
Mracková
G
G
Kadlubar
F F
FF
Vincze
I
I
D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers / Q000032:analysis*; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D018736:DNA Adducts / Q000097:blood; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D006814:Hungary / Q000453:epidemiology; D007527:Isoenzymes / Q000235:genetics; D008168:Lung / Q000601:surgery; D008175:Lung Neoplasms / Q000453:epidemiology / Q000378:metabolism / Q000601:surgery; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008669:Metallurgy; D016273:Occupational Exposure; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D011721:Pyrenes / Q000032:analysis; D012907:Smoking; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics
D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System; D018736:DNA Adducts; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; D011084:Polycyclic Aromatic Hydrocarbons; D011721:Pyrenes; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; C585496:CYP1B1 protein, human; C496556:GSTP1 protein, human; C033146:1-hydroxypyrene