Role of α Class Glutathione S-Transferases as Antioxidant Enzymes in Rodent Tissues

Abstract

Glutathione S-transferases (GST) are multifunctional proteins. α class GSTs are known to catalyze glutathione peroxidase reactions, in addition to their major activity, i.e., conjugation of electrophiles to glutathione. In the present work, the contribution of rat and mouse α class GSTs to glutathione-dependent reduction of phospholipid hydroperoxides has been studied., Results of these studies indicate that the α class GST fraction, which consists of three isoforms, has glutathione peroxidase activity toward phospholipid hydroperoxides residing in biological membranes, without the need of prior phospholipase C action. Immunotitration studies using antibodies specific to the α class GSTs, GSTA1-1, GSTA2-2, and GSTA3-3, indicate that these GST isozymes account for approximately half of the glutathione peroxidase activity toward phospholipid hydroperoxides present in the 28,000 g supernatant fractions of rat and mouse liver extracts. GSTs contribute proportionally lesser fraction of this activity in other tissues in which α class GSTs are less prevalent. In mice, the contribution of α class GSTs to the overall glutathione peroxidase activity is indistinguishable in wild-type mice and knockout mice lacking the major selenoenzyme, glutathione peroxidase 1, an enzyme that does not act on intact phospholipid hydroperoxides. These results are consistent with our previous studies on human α class GSTs (Yang, et al. J. Biol. Chem. 276, 19220–19230, 2001) and demonstrate that α class GSTs are of physiological importance, not only in the conjugative detoxification of electrophiles, but are also an essential component of cellular antioxidant defense mechanisms.