OXIDATIVE STRESS IN NONGENOTOXIC CARCINOGENESIS

The induction of oxidative stress in the target tissue has been propos ed as a possible mechanism of action for nongenotoxic carcinogens, A v ariety of nongenotoxic hepatocarcinogens including peroxisome prolifer ators, organochlorines, barbiturates, and metals have been shown to pr oduce an increase in reactive oxygen species (ROS) in the liver. Our g roup has examined the induction of oxidative stress by the organochlor ine mouse hepatic carcinogen, dieldrin. Using a salicylate spin trap a ssay, dieldrin was found to produce mouse liver-specific increases in ROS in cultured hepatocytes, Increased amounts of hepatic 8-hydroxy-2' -deoxyguanosine and malondialdehyde (MDA) and decreased levels of cell ular antioxidants were also seen in cultured mouse hepatocytes followi ng dieldrin treatment. In subchronically dieldrin-treated mice and rat s, hepatic vitamin E (Vit E) was decreased correlated with dieldrin do se, While Vit E levels were decreased in both rats and mice, the norma l lower levels of Vit E in the mouse resulted in a subsequent oxidativ e stress, evidenced by an increase in MDA formation in the mouse liver , Dieldrin also produced a dose-dependent increase in DNA synthesis in the mouse (not the rat) following subchronic treatment. These effects seen in both cells in culture and in vivo were species specific, orga n specific, and dose dependent which directly correlated with the obse rved pattern of cancer induction for dieldrin in rodents (mouse liver- specific). These findings support a possible role for the induction of oxidative stress in nongenotoxic hepatic carcinogenesis possibly thro ugh modulation of gene expression.