ABSTRACT
Oxidative DNA damage due to continuous generation of free radicals in cells that are responsive to peroxisome proliferators is the most rational mechanism responsible for peroxisome -proliferator-induced hepatocarcinogenesis (Rao and Reddy, 1987a; Reddy and Rao, 1986, 1989). Administration of peroxisome proliferators leads to an imbalance in the levels of free radical generating and scavenging enzymes in hepatic parenchymal cells resulting in excessive production of H2O2 and OH radicals (Ciriolo et al., 1982; Reddy et al., 1986b; Elliott et al.,
1986; Tomayewski et al., 1986; Osumi et al., 1987). Sustained induction of peroxisomal fatty acyl-CoA oxidase which generates H2O2, can lead to increased free radical generation, lipid peroxidation and DNA damage (Machlin and Bendich, 1987; Meneghini, 1988). Increased levels of lipofuscin and conjugated dienes, indicators of oxidative damage, are demonstrated in the livers of rats chronically treated with peroxisome proliferators (Reddy et al., 1982a; Goel et al., 1986; Lake et al., 1987; Conway et al., 1989). In vitro studies have shown induction of DNA strand breaks in hepatocytes by H 2O2 (Olson, 1988). In addition, it has been
demonstrated that peroxisomes isolated from livers of rats treated with peroxisome proliferators coincubated with SV40 DNA caused strand breaks (Fahl et al., 1984). Further direct evidence of free radical induced DNA damage is the demonstration of increased levels of 8 -hydroxydeoxyguanosine (8 -OHdG) in the livers of peroxisomeproliferator-treated rats (Kasai et al., 1989; Takagi et al., 1990a, b). 8-OHdG is considered as a marker for OH radical induced DNA alteration (Kasai and Nishimura, 1984). After treatment with peroxisome proliferators, higher levels of 8OHdG are observed only in the target organ liver, but not in non-target organs, which is consistent with the fact that peroxisome proliferation occurs predominantly in liver parenchymal cells (Takagi et al., 1990a, b). It is clear from these experimental observations that peroxisome proliferators are not capable of causing direct DNA damage, but they most likely induce DNA damage indirectly through their receptor mediated biological actions, which is of importance in hepatocarcinogenesis (Reddy and Rao, 1986; Lalwani et al., 1987; Issemann and Green, 1990).
