Glutathione Transferases

Abstract

This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous alpha,beta-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-kappaB (NF-kappaB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.

Genetic variation of genes for xenobiotic-metabolizing enzymes and risk of bronchial asthma: the importance of gene–gene and gene–environment interactions for disease susceptibility

“…These DNA sequences are highly conserved in most XME families and are known to regulate the expression profiles of XMEs in response to chemicals. 52 Certainly, the specific gametic correlations found in both study groups may be indirectly related to evolutionary forces. Instead, the differences in gametic correlations between the groups are suggestive of recent ecological and genetic events that have maintained such variable linkage disequilibrium between genes encoding XMEs in humans.…”

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

“…S2). GSTs play critical protective roles in cells by inactivating molecules capable of damaging various cellular components including proteins (Hayes et al ., 2005). It is possible that improved proteostasis in the three models evaluated in our studies is related at least in part to reduced accumulation of damaged proteins by virtue of increased or preserved GST synthesis and function.…”

Schisandra fructus extract ameliorates doxorubicin-induce cytotoxicity in cardiomyocytes: altered gene expression for detoxification enzymes

“…The compounds detoxified by GSTs include a broad range of carcinogens, anticancer drugs, metabolic byproducts, as well as environmental chemicals. Some GST isozymes, especially alpha class GSTs, can efficiently reduce fatty acid hydroperoxides as well as phospholipid hydroperoxides, and can disrupt the autocatalytic chain of lipid peroxidation by reducing these hydroperoxides that propagate lipid peroxidation chain reactions [10]. Furthermore, GST alpha 1 and alpha 2 can use membrane phospholipid hydroperoxides as substrates in situ and can protect cell membranes at the sites of damage.…”