Aging and enhanced hepatocarcinogenicity by peroxisome proliferator-activated receptor alpha agonists

The hepatocarcinogenic effect of PPARalpha agonists is enhanced by aging. Exposure to these chemicals produces a five- to seven-fold higher yield of grossly visible hepatic tumors in old relative to young animals. This review presents current experimental evidence, which supports a mechanism involving enhanced exposure to oxidative stress, and diminished apoptosis in this age-related difference in sensitivity. In the aged liver, a decrease in hepatic antioxidant activity, coupled with a PPARalpha agonist-induced increase in the activities of various oxidases, may expose these livers to oxidative stress. Additionally, livers of senescent animals appeared more sensitive to the anti-apoptotic effect of PPARalpha agonists. Since apoptosis safeguards cells with damaged DNA from progressing to the point of tumor formation, inhibition of hepatocellular apoptosis by PPARalpha agonists could well lead to the formation of focal lesions in the aged liver. Although PPARalpha-dependent alterations in cell cycle regulatory proteins have been reported, the correlation between hepatocellular DNA replication and liver cancer caused by PPARalpha agonists is a weak one. These findings have implications for human susceptibility to these chemicals.