Preferential use of less toxic detoxification pathways by long-lived species

This study was undertaken to determine whether the detoxification pathways producing the least oxidative stress appear to be favored in longer-lived mammalian species. Firstly, we focused on the cytochrome P-450 monooxygenase system. Although this system is an important component of the defenses that protect living organisms against toxic chemicals, some reactions catalyzed by the cytochrome P-450 system result in the formation of products that are highly reactive as well as active oxygen species. Our results suggest that the lower amount of hepatic cytochrome P-450 content found in longer-lived species may have evolved to reduce the toxic side-effect of this detoxification system. Support of the idea that the cytochrome P-450 system is an important source of oxidative stress is the positive correlation between cytochrome P-450 content and the amount of oxidized proteins found in liver of different human individuals. Secondly, we have measured the specific activity of other detoxification enzymes as a function of life span. Instead of a direct comparison of detoxification capabilities of the species, the approach used in this study was: (1) to select those detoxification enzymes which utilize the same substrate but differ in toxicity of the intermediate compounds formed in the reaction, and (2) to measure the levels of these enzymes in the two pathways to determine which pathway is dominant for each species. Our results suggest that the detoxification pathways producing the least oxidative stress do appear to be favored in longer-lived species.