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 would investigate several possible mechanisms for the age-dependent increase in allyl alcohol-induced liver injury. The studies would compare activities of key activation and detoxication enzymes in liver fractions prepared from mature, middle-aged and old male Fischer 344 rats (6, 18 and 30 months of age, respectively). In order to ascertain the toxicologic significance of age-related changes in enzyme activity, inhibitors of key steps in the activation/inactivation processes would be administered to the rats in vivo and their effects on allyl alcohol hepatotoxicity would be determined. Experiments would examine the effects of aging on alcohol dehydrogenase activity, NAD/NADH ratios and the inhibition of allyl alcohol toxicity by pyrazole. Age-dependent differences in covalent binding, time course of toxic events and contribution of the cytochrome P-450 system to allyl alcohol activation would also be investigated as possible reasons for the marked aging effect on hepatotoxicity. The role of aldehyde dehydrogenases in allyl alcohol detoxication would be studied by determining the effect of disulfiram administration on hepatotoxicity; the effects of aging on alcohol dehydrogenase activities would be determined, as well. In addition to the experiments aimed at elucidating mechanisms for the aging effect, others would determine the ability of the antinecrotic agents, N-acetylcysteine and butylated hydroxyanisole, to protect the aged liver from allyl alcohol-induced damage. 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 age differences in chemically induced liver disease and to identify compounds which can protect the aged liver from damage.
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