EFFECTS OF CALORIC RESTRICTION ON RODENT DRUG AND CARCINOGEN METABOLIZING ENZYMES - IMPLICATIONS FOR MUTAGENESIS AND CANCER

Caloric restriction in rodents results in increased longevity and a de creased rate of spontaneous and chemically induced neoplasia. The low rates of spontaneous neoplasia and other pathologies have made caloric ally restricted rodents attractive for use in chronic bioassays. Howev er, caloric restriction also alters hepatic drug metabolizing enzyme ( DME) expression and so may also alter the biotransformation rates of t est chemicals. These alterations in DME expression may be divided into two types: (1) those that are the direct result of caloric restrictio n itself and are detectable from shortly after the restriction is init iated; (2) those which are the result of pathological conditions that are delayed by caloric restriction. These latter alterations do not us ually become apparent until late in the life of the organism. In rats, the largest direct effect of caloric restriction on liver DMEs is an apparent de-differentiation of sex-specific enzyme expression. This in cludes a 40-70% decrease in cytochrome P450 2C11 (CYP2C11) expression in males and a 20-30% reduction of corticosterone sulfotransferase act ivity in females. Changes in DME activities that occur late in life in calorically restricted rats include a stimulation of CYP2E1-dependent 4-nitrophenol hydroxylase activity and a delay in the disappearance o f male-specific enzyme activities in senescent males. It is probable t hat altered DME expression is associated with altered metabolic activa tion of chemical carcinogens. For example the relative expression of h epatic CYP2C11 in ad libitum-fed or calorically restricted rats of dif ferent ages is closely correlated with the amount of genetic damage in 2-acetylaminofluorene- or aflatoxin B-1-pretreated hepatocytes isolat ed from rats of the same age and caloric intake. This suggests that al tered hepatic drug and carcinogen metabolism in calorically restricted rats can influence the carcinogenicity of test chemicals.