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The glutathione S-transferases: influence of polymorphism on cancer susceptibility
1Clinical Biochemistry Research Group, School of Postgraduate Medicine, Keele University, North Staffordshire Hospital, Stoke-on-Trent, United Kingdom.
Abstract:
The glutathione S-transferase supergene family is an important part of cellular enzymic defence against endogenous and exogenous chemicals, many of which have a carcinogenic potential. However, while a wide variety of chemicals can act as substrates for different members of the supergene family, the precise function of these enzymes remains unclear. The supergene family comprises several gene families that include polymorphic loci, prompting the hypothesis that allelic variants associated with less effective detoxification of potential carcinogens can confer an increased susceptibility to cancer. For example, the null genotypes at the mu class GSTM1 and theta class GSTT1 loci have attracted particular interest, and recently identified allelic variants at the mu class GSTM3 and pi class GSTP1 loci are also putative susceptibility candidates. However, while associations between GSTM1 and GSTT1 genotypes and risk have been observed in some case-control studies in lung, bladder and colon cancers, other studies have reported contrary findings, and the importance of these polymorphisms in mediating the risk of smoking-related cancers remains generally unproven. We describe the influence of glutathione S-transferase polymorphisms on the risk of several cancers, including basal cell carcinoma of skin. In the latter cancer, associations between tumour numbers, site and accrual have been observed, suggesting a role for GST enzymes in the detoxification of the products of ultraviolet radiation-induced oxidative stress. We review below current knowledge of polymorphism in GST loci, possible in vivo GST substrates, and the difficulties of determining the role of this complex gene family on the basis of available epidemiological data.
Insights
Glutathione S-transferase (GST) gene polymorphisms may influence cancer risk by affecting detoxification. However, evidence linking GST variants to cancer susceptibility, particularly smoking-related cancers, remains inconclusive.
Area of Science:
- Biochemistry
- Genetics
- Oncology
Background:
- The glutathione S-transferase (GST) supergene family provides cellular defense against harmful chemicals, including carcinogens.
- Polymorphisms within GST genes suggest that variations in detoxification efficiency could impact cancer susceptibility.
- Specific GST loci, such as GSTM1, GSTT1, GSTM3, and GSTP1, are investigated for their roles in cancer risk.
Purpose of the Study:
- To review the influence of glutathione S-transferase polymorphisms on the risk of various cancers.
- To explore the potential role of GST enzymes in detoxifying products of ultraviolet radiation-induced oxidative stress, particularly in basal cell carcinoma.
- To discuss current knowledge on GST gene polymorphisms, substrates, and the challenges in epidemiological data interpretation.
Main Methods:
- Review of existing literature on glutathione S-transferase gene polymorphisms and cancer risk.
- Analysis of epidemiological data, including case-control studies for lung, bladder, and colon cancers.
- Examination of associations between GST genotypes and basal cell carcinoma, considering tumor characteristics.
Main Results:
- Conflicting findings exist regarding the association between GSTM1 and GSTT1 genotypes and the risk of lung, bladder, and colon cancers.
- Evidence for the role of GST polymorphisms in mediating smoking-related cancer risk remains largely unproven.
- Associations between GST enzymes and basal cell carcinoma suggest a role in detoxifying UV-induced oxidative stress products.
Conclusions:
- The precise function of glutathione S-transferase enzymes and the impact of their polymorphisms on cancer risk require further investigation.
- Epidemiological data on GST polymorphisms and cancer susceptibility are often contradictory, highlighting the complexity of this gene family's role.
- GST enzymes may play a significant role in protecting against UV-induced oxidative damage, warranting further study in skin carcinogenesis.