Significance of genetic polymorphisms in glutathione S-transferase multigene family and lung cancer risk.

A vast number of studies are focused on investigating genetic polymorphism in order to estimate genetic contribution to the development of cancer. Possible cancer susceptibility genes have been sought among oncogenes, tumor suppressor genes, DNA repair genes and genes encoding phase I and phase II enzymes. Large individual differences in the biotransformation of xenobiotics have been explained on the basis of genetic polymorphisms in some detoxifying enzymes, regardless of environmental and occupational exposure. Among these enzymes, glutathione S-transferases (GST) constitute a large multigene family of phase II enzymes involved in detoxification of potentially genotoxic chemicals. Five genetic polymorphisms of GST have been well documented. Total or partial deletions and (or) single nucleotide polymorphisms in alleles encoding GSTM1, GSTM3, GSTPI, GSTT1, GSTZ1 are associated with reduction of enzymatic activity toward several substrates of different GST isoenzymes. In addition, molecular epidemiology studies indicate that a single genetic polymorphism of glutathione S-transferase appears to be a moderate lung cancer risk factor. However, the risk is higher when interactions with more GST polymorphisms and other risk factors (e.g. cigarette smoking) occur. Individuals with decreased rate of detoxification, with "high risk" glutathione S-transferase genotypes have a slightly higher level of carcinogen-DNA adducts and more cytogenetic damages.