The glutathione transferases (GSTs; also known as glutathione S-transferases) are major phase II detoxification enzymes found mainly in the cytosol. In addition to their role in catalysing the conjugation of electrophilic substrates to glutathione (GSH), these enzymes also carry out a range of other functions. They have peroxidase and isomerase activities, they can inhibit the Jun N-terminal kinase (thus protecting cells against H(2)O(2)-induced cell death), and they are able to bind non-catalytically a wide range of endogenous and exogenous ligands. Cytosolic GSTs of mammals have been particularly well characterized, and were originally classified into Alpha, Mu, Pi and Theta classes on the basis of a combination of criteria such as substrate/inhibitor specificity, primary and tertiary structure similarities and immunological identity. Non-mammalian GSTs have been much less well characterized, but have provided a disproportionately large number of three-dimensional structures, thus extending our structure-function knowledge of the superfamily as a whole. Moreover, several novel classes identified in non-mammalian species have been subsequently identified in mammals, sometimes carrying out functions not previously associated with GSTs. These studies have revealed that the GSTs comprise a widespread and highly versatile superfamily which show similarities to non-GST stress-related proteins. Independent classification systems have arisen for groups of organisms such as plants and insects. This review surveys the classification of GSTs in non-mammalian sources, such as bacteria, fungi, plants, insects and helminths, and attempts to relate them to the more mainstream classification system for mammalian enzymes. The implications of this classification with regard to the evolution of GSTs are discussed.

The glutathione transferases (GSTs; also known as glutathione S-transferases) are major phase II detoxification enzymes found mainly in the cytosol. In addition to their role in catalysing the conjugation of electrophilic substrates to glutathione (GSH), these enzymes also carry out a range of other functions. They have peroxidase and isomerase activities, they can inhibit the Jun N-terminal kinase (thus protecting cells against H2O2-induced cell death), and they are able to bind non-catalytically a wide range of endogenous and exogenous ligands. Cytosolic GSTs of mammals have been particularly well characterized, and were originally classified into Alpha, Mu, Pi and Theta classes on the basis of a combination of criteria such as substrate/inhibitor specificity, primary and tertiary structure similarities and immunological identity. Non-mammalian GSTs have been much less well characterized, but have provided a disproportionately large number of three-dimensional structures, thus extending our structure–function knowledge of the superfamily as a whole. Moreover, several novel classes identified in non-mammalian species have been subsequently identified in mammals, sometimes carrying out functions not previously associated with GSTs. These studies have revealed that the GSTs comprise a widespread and highly versatile superfamily which show similarities to non-GST stress-related proteins. Independent classification systems have arisen for groups of organisms such as plants and insects. This review surveys the classification of GSTs in non-mammalian sources, such as bacteria, fungi, plants, insects and helminths, and attempts to relate them to the more mainstream classification system for mammalian enzymes. The implications of this classification with regard to the evolution of GSTs are discussed.

Oesophageal carcinoma is a common form of cancer in developing countries, especially in the Caspian littoral and northern China. In contrast, it has a much lower incidence in Japan, the U.S.A. and western Europe. Certainly in the case of squamous cell oesophageal carcinoma, dietary composition, smoking, alcohol and exposure to nitrosamines are major risk factors that may partly explain the disease's geographical distribution. The prognosis for oesophageal carcinoma is generally poor, due to the high incidence of distant metastasis and local recurrence. Combination treatment with both cisplatin and 5-fluorouracil is the most common chemotherapy regime used. We have carried out a detailed study of sensitivity of two oesophageal cell lines: OC1 cells from a squamous carcinoma of a male patient, and OC2, a squamous carcinoma obtained from a female patient. Both cell lines are sensitive to Vinca alkaloids and doxorubicin, while being quite resistant to alkylating agents such as cisplatin and 1,3-bis-(2-chloroethyl)-1-nitrosourea. This pattern of resistance suggests a possible role for glutathione S-transferase (GST) and/or glutathione (GSH) in resistance, and would seem to exclude the multidrug resistance phenotype. Both cell lines possess mainly Pi-class GSTs, and have distinct levels of GSH, with OC2 possessing some 25% of the level of OC1 cells. Effects of a variety of modulating agents on the pattern of resistance, such as the GSH depleter, buthionine sulphoximine, and the GST inhibitor, ethacrynic acid, were determined. An unexpected observation was that ethacrynic acid appears to increase the level of GSH in both cell lines.

Age related deterioration in immune function has been recognised in many species. In humans the clinical manifestations of such immune dysfunction is an age-related increase in the susceptibility to certain infections, the incidence of some autoimmune diseases and certain cancers. Laboratory investigations reveal age-related changes in the peripheral T cell pool, in the predominant phenotype, cytokine production profiles, signaling function, and in replicative ability following stimulus with antigen, mitogens or anti CD3 antibody. These changes in the properties of peripheral T cells are thought to be causally linked to an age-associated involution in the thymus. Our analysis reveals that thymic involution is due to a change in the thymic microenvironment linked to a reduction in the levels of available IL-7. Treatment with IL-7 leads to a reversal of thymic atrophy with increased thymopoiesis. This provides the potential to reverse the immune dysfunction seen in the peripheral T cell pool by replacing old T cells with new output generated by the thymus. Problems to overcome for such an experimental therapy to be successful require careful analysis in order to provide an optimal strategy to ensure that new T cell emigrants from the thymus have a broad range of specificities and are able to enter the peripheral T cell pool.

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