Toxicology of Industrial Compounds

226 PEROXISOME PROLIFERATION
demonstrated to be effective in rat liver tumour promotion studies (Cattley
and Popp, 1989; Bentley et al., 1993; Popp and Cattley, 1993).
Mechanisms of hepatocarcinogenesis
Several hypotheses have been proposed to account for why peroxisome
proliferators can produce liver tumours in rodents. These mechanisms
include:
(a) Induction of sustained oxidative stress to hepatocytes (Reddy and
Lalwani, 1983; Reddy and Rao, 1989).
(b) A role of increased cell proliferation (Marsman et al., 1988; Popp and
Marsman, 1991).
(c) The promotion of spontaneously formed preneoplastic liver lesions
(Schulte-Hermann et al., 1989; Cattley et al., 1991; Grasl-Kraupp et
al., 1993).
(d) A combination of two or all of the above factors.
The oxidative stress hypothesis is based on the observation that the chronic
administration of peroxisome proliferators produces a sustained oxidative
stress in rodent hepatocytes due to an imbalance in the production and
degradation of hydrogen peroxide (Reddy and Lalwani, 1983; Reddy and
Rao, 1989). Peroxisome proliferators markedly induce the peroxisomal
fatty acid β-oxidation cycle, but produce only a small increase in catalase
activity. The first enzyme of the β-oxidation cycle, acyl-CoA oxidase,
produces hydrogen peroxide and hence the cyclic oxidation of a single fatty
acid molecule can result in the production of several molecules of hydrogen
peroxide (Lazarow and DeDuve, 1976). Any excess hydrogen peroxide not
destroyed by peroxisomal catalase can diffuse through the peroxisomal
membrane into the cytosol where it will be a substrate for cytosolic
selenium-dependent glutathione peroxidase. However, this enzyme activity
and that of other enzymes including superoxide dismutase and glutathione
S-transferases are often reduced by the administration of peroxisome
proliferators to rodents (Reddy and Rao, 1989; Bentley et al., 1993; Lake,
1993). These enzyme changes are postulated to result in increased
intracellular levels of hydrogen peroxide which, either directly or via
reactive oxygen species (e.g. hydroxyl radical), can attack membranes and
DNA (Reddy and Lalwani, 1983; Reddy and Rao, 1989).
A number of experimental observations have provided support for the
involvement of oxidative stress in the hepatotoxicity of peroxisome
proliferators (Reddy and Rao, 1989; Lake, 1993). For example,
peroxisome proliferators have been reported in some studies to increase
hepatic lipid peroxidation and lipofuscin deposition, to modulate levels of
hepatic antioxidants and to increase levels of 8-hydroxydeoxyguanosine in