Glutathione Transferases, Detoxication, Cancer and Longevity

Glutathione transferases (GSTs) were discovered 50 years ago as enzymes capable of conjugating electrophilic organic substances with the thiol group of glutathione. Early on GSTs were identified as prominent detoxication enzymes that protect cells against mutagens and carcinogens. Our research established that products of lipid peroxidation and other oxidative processes are natural substrates of the enzymes. In humans GST A4-4 and GST M2-2 appear to have evolved specifically for inactivation of 4-hydroxynonenal and ortho-quinones of catecholamines, respectively, as evidenced by their distinctive high activities with the substrates. It would appear that GSTs counter the effects of oxidative stress associated with numerous degenerative conditions such as Parkinson and Alzheimer disease, cataract, atherosclerosis, diabetes, and cancer. In tumor cells GSTs can cause resistance against alkylating anti-cancer drugs. Engineered GSTs with enhanced activity against cytostatic drugs may find medical applications in gene therapy and in the activation of prodrugs. Long-lived strains of eukaryotes are characterized by overexpression of a subset of GSTs. It is possible that longevity of humans is also correlated with the expression of certain GSTs and that pharmacological interventions may influence health and life-span by enhanced detoxication capacity of toxic compounds occurring in tissues.