Preliminary studies in rats indicated that old age modifies the response of the liver to certain types of chemical injury. The effects were most pronounced for allyl alcohol hepatotoxicity, which increased dramatically as a function of age. The present proposal will investigate several possible mechanisms for the age-dependent increase in allyl alcohol-induced liver injury. The studies will compare activities of key activation and detoxification enzymes in liver fractions prepared from young, middle-aged and old male Fischer 344 rats (4, 14 and 25 months of age, respectively). Experiments to determine if aging is associated with increased activation of allyl alcohol to its toxic metabolite, acrolein, will continue. The effect of testosterone administration on hepatic alcohol dehydrogenase activity and allyl alcohol toxicity will be determined. Also, NAD/NADH ratios, which also influence the metabolism of allyl alcohol by alcohol dehydrogenase, will be measured in livers of young, middle-aged and old rats. The role of aldehyde dehyrogenases in acrolein detoxification will be examined by determining the effect of aldehyde dehydrogenase inhibitors on allyl alcohol hepatotoxicity. The effect of aging on these enzymes will be measured, as well. Finally, experiments will be conducted to ascertain whether the time course of toxic events occurring after allyl alcohol administration is affected by the aging process. Understanding how aging affects the susceptibility of the liver to chemical injury is of importance to geriatric medicine. The long-term goal of this research is to establish mechanisms responsible for aging differences in chemically induced liver disease and to identify compounds which can protect the aged liver from damage.
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