Effect of glutathione S-transferase M1 polymorphisms on biomarkers of exposure and effects

Abstract

Genotypes responsible for interindividual differences in ability to activate or detoxify genotoxic agents are recognized as biomarkers of susceptibility. Among the most studied genotypes are human glutathione transferases. The relationship of genetic susceptibility to biomarkers of exposure and effects was studied especially in relation to the genetic polymorphism of glutathione S-transferase M1 (GSTM1). For this review papers reporting the effect of GSTM1 genotype on DNA adducts, protein adducts, urine mutagenicity, Comet assay parameters, chromosomal aberrations, sister chromatid exchanges (SCE), micronuclei, and hypoxanthine-guanine phosphoribosyl transferase mutations were assessed. Subjects in groups occupationally exposed to polycyclic aromatic hydrocarbons, benzidine, pesticides, and 1,3-butadiene were included. As environmentally exposed populations, autopsy donors, coal tar-treated patients, smokers, nonsmokers, mothers, postal workers, and firefighters were followed. From all biomarkers the effect of GSTM1 and N-acetyl transferase 2 was seen in coke oven workers on mutagenicity of urine and of glutathione S-transferase T1 on the chromosomal aberrations in subjects from 1,3-butadiene monomer production units. Effects of genotypes on DNA adducts were found from lung tissue of autopsy donors and from placentas of mothers living in an air-polluted region. The GSTM1 genotype affected mutagenicity of urine in smokers and subjects from polluted regions, protein adducts in smokers, SCE in smokers and nonsmokers, and Comet assay parameters in postal workers. A review of all studies on GSTM1 polymorphisms suggests that research probably has not reached the stage where results can be interpreted to formulate preventive measures. The relationship between genotypes and biomarkers of exposure and effects may provide an important guide to the risk assessment of human exposure to mutagens and carcinogens.

Meta-analysis and pooled analysis of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers: a HuGE-GSEC review

“…However, there is no consistent evidence supporting this association. Some studies have found a higher level of DNA adducts and chromosome damage in lymphocytes of coke oven workers, bus drivers and tobacco smokers who lack the GSTM1 gene, 24,[105][106][107][108] whereas others failed to find a significant relationship. 109,110 The same can be said for CYP1A1 polymorphisms.…”

Genotypes of glutathione S-transferase M1 and N-acetyltransferase 2 in Japanese patients with gastric cancer

“…The age range of the patients with gastric cancer was 30-84 years (mean age, 62.5 Ϯ 11.3 years; there were 98 men and 49 women). The control study with age-matched autopsy subjects (age at death, 20-95 years; mean age, 64.0 Ϯ 17.5 years; 74 men and 38 women) excluded patients with stomach, lung, urinary bladder, or colon cancer, because several studies have indicated that GSTM1 deficiency is a risk factor for the development of these cancers [1,3,5]. Smoking histories were not available in this study, because the information was incomplete in a considerable number of the cases and controls.…”

“…Glutathione S-transferase M1 (GSTM1), a member of the GST mu family, is one of the most studied genotypes in relation to the individual susceptibility to cancers. For example, a considerable number of investigations indicate that individuals with a homozygous deletion of the GSTM1 gene (GSTM1 null genotype) are susceptible to lung and urinary bladder cancers [1,3,5]. However, the link between the GSTM1 polymorphism and gastric carcinoma is controversial [6][7][8][9][10].…”

Relationship between genetic polymorphisms of metabolizing enzymes CYP2E1, GSTM1 and Kazakh’s esophageal squamous cell cancer in Xinjiang, China

“…Glutathione S-transferases (GSTs) are phase II enzymes and responsible for catalyzing the biotransformation of a variety of electrophiles, and have a central role in the detoxification of activated metabolites of procarcinogens produced by phase I reactions. GSTM1 conjugates xenobiotics with glutathione [4] which promotes the removal of activated carcinogens from the human body. Esophageal cancer (EC) is one of the most common malignant diseases worldwide with a sharp variation in its geographic distribution [5] .…”