Modulation of chemical toxicity by modification of caloric intake.

Caloric restriction increases maximum achievable lifespan and offsets the time to development of degenerative disease. Part of these desirable effects may result from positive modulation of toxic events. We have shown that when rodents are placed on a diet that is reduced in total calories by 40%, several beneficial changes on biochemical systems which impact on toxicologic processes are positively enhanced. Lipid metabolism is reduced and, therefore, the potential for lipoperoxidation is reduced. Additionally, activity of enzymes that produce free radicals as byproducts (cytochrome P4502C11) are also reduced. Concurrently, we have shown that the "effective" activity of catalase and the activity of superoxide dismutase (which are required for the detoxification of toxic oxygen radicals) are significantly increased by caloric restriction. The activities of enzymes of drug and xenobiotic metabolism are also altered by caloric restriction. The effect upon activity may be to either decrease or increase activity, dependent upon whether the enzyme activates compounds to intermediates which may be more toxic or whether the enzyme acts to reduce toxicity. We have also shown that caloric restriction may affect the initiation stage of carcinogenesis. Aflatoxin B1 binding to hepatic nuclear DNA was reduced by caloric restriction (caloric restriction reduced both major adducts that are formed upon exposure to aflatoxin B1). caloric restriction also reduced cytochrome P4502C11 which converts aflatoxin B1 to its toxic epoxide, and may partly explain the reduction in binding. These results suggest that caloric restriction may, in part, extend the time to development of degenerative disease by altering basic biochemical mechanisms of toxicity.