Nafenopin-Induced Hepatic Microbody (Peroxisome) Proliferation and Catalase Synthesis in Rats and Mice

Abstract

Nafenopin (2-methyl-2[p-(1,2,3,4-tetrahydro-l-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 (Csa strain) mice and acatalasemic (Csb 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 Csa 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-a-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 All the above effects of nafenopin were fully reversed when the drug was withdrawn from the diet of male rats .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 .

Fine Structural Changes in the Hepatic Microbodies of Rats Treated With Hypolipidemic Agents, Gemfibrozil and Clofibrate

“…Proliferation of microbodies due to the effect of several hypolipidemic agents has been examined by biochemical assay of catalase (7), by electron microscopic cytochemistry (24) and more recently by morphometric analysis (18,29).…”

“…It is well documented that a marked increase in the number of hepatic microbodies is observed following administrations with hypolipidemic agents, such as clofibrate (7,20,30), simfibrate (8,9), S-8527 (28) and nafenopin (1,14,24). It has been suggested that the microbody proliferation induced by hypolipidemic drugs was related to their pharmacological effects (21)) .…”

Autophagy in organelle homeostasis: Peroxisome turnover

“…phthalate ester (DEHP). After withdrawal of the proliferators in 2 weeks, the number of peroxisomes dramatically decreases in rat liver cells (Reddy et al,1974;Yokota1993). Apparently the massive proliferation of peroxisomes has necessitated the cell's maintenance of regulatory pathways to precisely control organelle activity and abundance.…”

Tumorigenicity of the hypolipidaemic peroxisome proliferator ethyl-α-p-chlorophenoxyisobutyrate (clofibrate) in rats

“…After fixation, the tissues were dehydrated in ethanol and processed as described previously (Reddy et al, 1974b). For cytochemnical localization of peroxisome catalase, selected samples of liver and liver tumours w-ere processed as described by Novikoff & Goldfischer (1969 showed pulmonary metastases (Fig.…”