NAFENOPIN-INDUCED HEPATIC MICROBODY (PEROXISOME) PROLIFERATION AND CATALASE SYNTHESIS IN RATS AND MICE : Absence of Sex Difference in Response

Nafenopin (2-methyl-2[p-(1,2,3,4-tetrahydro-1-naphthyl)phenoxy]-propionic acid; Su-13437), a potent hypolipidemic compound, was administered in varying concentrations in ground Purina Chow to male and female rats, wild type (Cs^a strain) mice and acatalasemic (Cs^b strain) mice to determine the hepatic microbody proliferative and catalase-inducing effects. In all groups of animals, administration of nafenopin at dietary levels of 0.125% and 0.25% produced a significant and sustained increase in the number of peroxisomes. The hepatic microbody proliferation in both male and female rats and wild type Cs^a strain mice treated with nafenopin was of the same magnitude and was associated with a two-fold increase in catalase activity and in the concentration of catalase protein. The increase in microbody population in acatalasemic mice, although not accompanied by increase in catalase activity, was associated with a twofold increase in the amount of catalase protein. The absence of sex difference in microbody proliferative response in nafenopin-treated rats and wild type mice is of particular significance, since ethyl-α-p-chlorophenoxyisobutyrate (CPIB)-induced microbody proliferation and increase in catalase activity occurred only in males. Nafenopin can, therefore, be used as an inducer of microbody proliferation and of catalase synthesis in both sexes of rats and mice. The serum glycerol-glycerides were markedly lowered in all the animals given nafenopin, which paralleled the increase in liver catalase. All the above effects of nafenopin were fully reversed when the drug was withdrawn from the diet of male rats. During reversal, several microbody nucleoids were seen free in the hyaloplasm or in the dilated endoplasmic reticulum channels resulting from a rapid reduction in microbody matrix proteins after the withdrawal of nafenopin from the diet. Because of microbody proliferation and catalase induction with increasing number of hypolipidemic compounds, additional studies are necessary to determine the interrelationships of microbody proliferation, catalase induction, and hypolipidemia.