Biochemical studies on the mechanisms by which dietary antioxidants suppress mutagenic activity

Abstract

The protection afforded by antioxidants against the induction of a variety of experimental tumors in rodents in a phenomenon on great theoretical interest and potentially of practical importance. The possibility that the antioxidants exert their effects by interacting directly with the electrophilic species of ultimate carcinogens cannot be excluded. However, at present the most plausible mechanisms for the protective effects of antioxidants invoke alteration of the balance between metabolic activation and inactivation of the carcinogens. Dietary administration of 2(3)- tert-butyl-4-hydroxyanisole (BHA) to mice results in a marked reduction in the levels of mutagenic metabolites of benzo(a)pyrene prevailing in theurine and in the peritoneal cavity. This dietary treatment is accompanied by substantial elevations in the levels of various glutathione S-transferase and epoxide hydratase in the livers and a number of other tissues of mice and rats. Direct addition of glutathione and certain purified glutathione S-transferases to the mutagenicity assay system reduces the mutagenic activity of the urinary metabolites of benzo(a)pyrene. Others have shown that epoxide hydratase can function in both the metabolic activation and inactivation of this carcinogen. Other changes in the activities of mouse hepatic enzymes associated with the feeding of BHA include the elevations in UDP-glucose dehydrogenase and UDP-glucuronyl transferase activities suggesting an enhanced capacity for glucuronide formation.