A Scientific Basis for Cancer Prevention: Defining the Role of Individual Cytosolic GST Isozyme

Highly electrophilic functional groups of exogenous and endogenous chemicals represent a significant threat to the structural integrity of DNA because of their propensity to react with nucleophilic sites on DNA bases. The accumulation of electrophile-mediated DNA lesions in cellular-growth regulatory genes, and their expression-controlling elements with ensuing dysregulation of growth, has been proposed as a common pathway leading to neoplastic transformation (1 ). Glutathione S-transferases (GSTs) are a large family of cytosolic and microsomal enzymes that share the common ability to catalyze the formation of thioether conjugates of glutathione (GSH) with a wide array of structurally unrelated electrophilic toxins (including several known carcinogens and mutagens), but which differ in catalytic efficiencies toward different electrophilic substrates and in other non-S-transferase catalytic activities (2 ). Numerous animal studies showing increased tissue GST activity in response to electrophilic carcinogen exposure indicate that GSTs may function as a primary defense mechanism for protecting nucleophilic groups on DNA bases from mutagenic electrophiles (2 ,3 ). A strong correlation between the ability of dietary phenolic antioxidants to preferentially induce phase II biotransformation enzymes such as GSTs, and their ability to prevent neoplasm induced by subsequent chemical carcinogen exposure, further supports the idea that GSTs serve an important role in defending DNA from electrophilic toxins (2 ,3 ). These studies as well as mechanistic studies, which have linked the regulation of expression of GST isozymes with the Michael-acceptor electrophilic functional groups of carcinogens, phenolic antioxidants, and their metabolites (3 ), have laid a foundation for defining optimal strategies for cancer prevention by altering the expression of GST isozymes through pharmacologic and dietary means.