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Glutathione S-transferase in chemotherapy resistance and in carcinogenesis
R L Schecter1, M A Alaoui-Jamali, G Batist
1Department of Medicine, Montréal General Hospital Research Institute-McGill University, Que., Canada.
Abstract:
Cytosolic glutathione S-transferases are composed of two monomeric subunits. These monomers are the products of different gene families designated alpha, mu, and pi. Dimerization yields either homodimeric or heterodimeric holoenzymes within the same family. The members of this complex group of proteins have been linked to the detoxification of environmental chemicals and carcinogens, and have been shown to be overexpressed in normal and tumor cells following exposure to cytotoxic drugs. They also are overexpressed in carcinogen-induced rat liver preneoplastic nodules in rat liver. In all of these cases, the changes in expression of glutathione S-transferases are paralleled by increased resistance to cytotoxic chemicals. The degree of resistance is related to the substrate specificity of the isozyme. The relationship of the glutathione S-transferase genes to drug resistance has been directly demonstrated by gene transfer studies, where cDNAs encoding the various subunits of glutathione S-transferase have been transfected into a variety of cell types. This review discusses the results of numerous studies that associate resistance to alkylating agents with overexpression of protective detoxifying glutathione S-transferase enzymes.
Insights
Glutathione S-transferases (GSTs) detoxify harmful chemicals. Overexpression of these enzymes increases cellular resistance to cytotoxic drugs and carcinogens, a key factor in drug resistance.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- Cytosolic glutathione S-transferases (GSTs) are crucial enzymes involved in detoxification.
- GSTs exist as homodimeric or heterodimeric holoenzymes, formed from alpha, mu, and pi gene families.
- Increased GST expression is observed in cells exposed to cytotoxic drugs and in carcinogen-induced liver nodules.
Purpose of the Study:
- To review the association between glutathione S-transferase gene expression and cellular resistance to cytotoxic agents.
- To highlight the role of GSTs in detoxification of environmental chemicals and carcinogens.
Main Methods:
- Review of numerous studies investigating GST expression and drug resistance.
- Analysis of gene transfer studies demonstrating the link between GSTs and drug resistance.
Main Results:
- Overexpression of GSTs correlates with increased resistance to cytotoxic chemicals.
- The degree of resistance is dependent on the substrate specificity of the specific GST isozyme.
- Gene transfer studies confirm the direct relationship between GST genes and drug resistance.
Conclusions:
- Glutathione S-transferases play a significant role in cellular defense mechanisms against toxic substances.
- Understanding GST function is critical for developing strategies to overcome drug resistance in cancer therapy.