Human Alpha Class Glutathione S‐Transferases: Genetic Polymorphism, Expression, and Susceptibility to Disease

Abstract

The human alpha class glutathione S-transferases (GSTs) consist of 5 genes, hGSTA1-hGSTA5, and 7 pseudogenes on chromosome 6p12.1-6p12.2. hGSTA1-hGSTA4 have been well characterized as proteins, but hGSTA5 has not been detected as a gene product. hGSTA1-1 (and to a lesser extent hGSTA2-2) catalyzes the GSH-dependent detoxification of carcinogenic metabolites of environmental pollutants and tobacco smoke (e.g., polycyclic aromatic hydrocarbon diolepoxides) and several alkylating chemotherapeutic agents and has peroxidase activity toward fatty acid hydroperoxides (FA-OOH) and phosphatidyl FA-OOH. hGSTA3-3 has high activity for the GSH-dependent Delta(5)-Delta(4) isomerization of steroids, and hGSTA4-4 has high activity for the GSH conjugation of 4-hydroxynonenal. hGSTA4 is expressed in many tissues; hGSTA1-1 and hGSTA2-2 are expressed at high levels in liver, intestine, kidney, adrenal gland, and testis; and hGSTA3 is expressed in steroidogenic tissues. Functional, allelic, single nucleotide polymorphisms occur in an SP1-binding element of hGSTA1 and in the coding regions of hGSTA2 and hGSTA3. The main effects of these polymorphisms are the low hepatic expression of hGSTA1 in individuals homozygous for hGSTA1*B and the low specific activity of the hGSTA2E-2E variant toward FA-OOH. These properties suggest that alpha class GSTs will be involved in susceptibility to diseases with an environmental component (such as cancer, asthma, and cardiovascular disease) and in response to chemotherapy. Although hGSTM1, hGSTT1, and hGSTP1 have been associated with such diseases (on the basis of genetic polymorphisms as indicators of expression), alpha class GSTs have been little studied in this respect. Nevertheless, hGSTA1*B has been associated with increased susceptibility to colorectal cancer and with increased efficacy of chemotherapy for breast cancer. Methods for identification and quantitation of human alpha class GST protein, mRNA, and genotype are reviewed, and the potential for GST-alpha in plasma to be used as a marker for hepatic expression and induction is discussed.