Cultured hepatocytes for studies of peroxisome proliferation: methods and applications.

Numerous compounds including pharmaceutical agents, herbicides, and plasticizers have been identitied as peroxisome proliferators in rodents (Each0 and Feller, 1991; Lake et al., 1984; Lalwani et al., 1983; Moody and Reddy, 1978). The hepatic effects of these compounds include increases in the number and size of hepatic peroxisomes, hepatomegaly, hepatocellular hypertrophy, and increased rates of hepatocyte replication. There are also increases in the volume and surface area of the smooth endoplasmic reticulum and mitochondria (Hess et al., 1965; Lipsky and Pedersen, 1982; Svoboda and Azarnoff, 1966). The major biochemical effects are on enzymes associated with lipid metabolism. Mitochondrial and peroxisomal fatty acid B-oxidation, carnitine acetyltransferase, and microsoma1 lauric acid hydroxylase activity (Lazarow, 1977; Lazarow and de Duve, 1976; Moody and Reddy, 1978; Orton and Parker, 1982) increase tento 40-fold. In contrast, the activity of catalase, the most abundant protein of the peroxisome, is generally increased twofold or less. Peroxisome proliferators increase the incidence of hepatocellular carcinomas in rats and mice after chronic administration (Reddy and Lalwani, 1983; Reddy and Rao, 1977; Reddy et al., 1976). In general, the potency of a compound for peroxisome proliferation correlates with its hepatocarcinogenicity. The mechanism of the carcinogenesis is not yet understood. The compounds are consistently negative in short-term genotoxicity tests including the Ames assay (Glauert et al., 1984; Warren et al., 1980), sister chromatid exchange (Linnainmaa, 1984), DNA repair (Butterworth et al., 1984; Cattley et al., 1986; Glauert et al., 1984),