Influence of aging on chemically induced hepatotoxicity: role of age-related changes in metabolism

The effects on hepatotoxicity of age-associated changes in drug metabolism are not always straightforward. In the case of allyl alcohol hepatotoxicity in male rats, there is a good relationship between increased metabolic activation by liver alcohol dehydrogenase and enhanced hepatotoxicity in old age. With regard to two other hepatotoxicants, some tentative conclusions about the role of metabolism can be drawn, but they must be tempered with caution due to gaps in the available information. Acetaminophen-induced hepatotoxicity is reduced in old age, and decreased formation of the toxic intermediate may be the reason. There is a prominent effect of aging on acetaminophen conjugation, a shift from sulfation to glucuronidation, but this change does not affect total clearance. The situation with carbon tetrachloride is difficult to interpret because the final outcome is unaltered hepatotoxicity in old age. Nevertheless, the available data suggest that an age-associated decrease in activation of carbon tetrachloride is counterbalanced by a loss in resistance to lipid peroxidation. These conclusions are summarized in Table 5. Again, it must be emphasized that all of these age-dependent changes in toxicity could be related to effects on other systems that are not necessarily involved in the metabolism of hepatotoxicants. Future research is needed to identify pathways of metabolic activation and detoxification in which age-dependent changes occur that result in significant changes in hepatotoxicity. The entire sequence of events from changes at the molecular level to their sequelae at the level of the cell, tissue and intact animal should be investigated, and the results should be confirmed in more than one mammalian model of aging. The aim would be to identify basic mechanisms that result in increased hazard for the aged liver from exposure to toxic compounds.