Cytogenetic Markers of Susceptibility: Influence of Polymorphic Carcinogen-
metabolizing Enzymes
Hannu Norppa
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland
Abstract
Polymorphisms of xenobiotic-metabolizing enzymes, responsible for individual differences in metabolic activation and detoxification reactions, may profoundly modulate the effects of chemical carcinogens. In the case of genotoxic carcinogens, differences in biological effects due to genetic polymorphisms can be evaluated by cytogenetic methods such as the analysis of chromosomal aberrations (CAs), sister chromatid exchanges (SCEs), micronuclei (MN), and changes in chromosome number. These techniques can be applied to any exposure known to induce such alterations, without additional method development for each exposing agent. The influence of polymorphic genes on the cytogenetic effects of a carcinogen can quickly be tested in vitro using metabolically competent cells collected from donors representing different genotypes or phenotypes. For instance, erythrocytes from individuals positive for glutathione S-transferase T1 (GSTT1) express GSTT1, whereas GSTT1-null donors, having a homozygous deletion of the GSTT1 gene, completely lack this detoxification enzyme. This deficiency results in highly increased sensitivity to SCE induction in whole-blood lymphocyte cultures by 1,2:3,4-diepoxybutane, a reactive metabolite of 1,3-butadiene. The same cytogenetic techniques can also be applied as effect biomarkers in studies of human populations exposed to genotoxic carcinogens. For example, elevated rates of chromosome damage have been detected among smokers lacking glutathione S-transferase M1 (GSTM1-null genotype), and the baseline level of SCEs seems to be increased in GSTT1-null individuals. Information obtained from cytogenetic studies of genetic polymorphisms can be used, for example, to recognize the genotoxically relevant substrates of the polymorphic enzymes, to identify genotypes that are susceptible to these genotoxins, to improve in vitro genotoxicity tests utilizing human cells, to increase the sensitivity of cytogenetic endpoints as biomarkers of genotoxic effects in humans, and to direct mechanistic studies and cancer epidemiology. -- Environ Health Perspect 105(Suppl 4):829-835 (1997)
Key words: biomarkers, carcinogens, chromosome aberrations, genetic polymorphisms, genotoxicity, glutathione S-transferases, individual susceptibility, micronuclei, sister chromatid exchanges
This paper was prepared as background for the Workshop on Susceptibility to Environmental Hazards convened by the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC) held 17-22 March 1996 in Espoo, Finland. Manuscript received at EHP 5 November 1996; accepted 18 November 1996.
Address correspondence to Dr. H. Norppa, Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, FIN-00250 Helsinki, Finland. Telephone: 358-9-4747336. Fax: 358-9-4747208. E-mail: hnor@occuphealth.fi
Abbreviations used: ALDH2, aldehyde dehydrogenase 2; CAs, chromosomal aberrations; CYP1A1, cytochrome P4501A1; CYP2D6, cytochrome P-4502D6; FISH, fluorescence in situ hybridization; GSTM1, glutathione S-transferase M1; GSTT1, glutathione S-transferase T1; MN, micronuclei; NAT2, N-acetyltransferase 2; SCEs, sister chromatid exchanges.
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Last Update: June 17, 1997