Increase of muscle peroxisomal enzymes and myotonia induced by nafenopin, a hypolipidemic drug.

The chronic administration of nafenopin, a hypolipidemic drug, induced an increase in catalase and acyl-CoA oxidase activities in various skeletal muscles, including the gracilis, diaphragm, soleus, and extensor digitorum longus. The magnitude of the increase was around 100% for both enzymes in each of the muscles studied in spite of the different basal level. These changes seem to be specific of the peroxisomal enzymes because acetylcholinesterase, which is not peroxisomal, did not follow the same pattern in all the muscles. Concomitant with the increase in muscle peroxisomal enzymes, the skeletal muscles presented an altered electromyogram with prolonged insertional activity, repetitive firing of action potentials, and myotonic runs characteristic of myotonia. Our results suggest a role for peroxisomes in the myotonic disorder.

Malignant tumors in rats fed nafenopin, a hepatic peroxisome proliferator.

Nafenopin (2-methyl-2-[P-(1,2,3,4-tetrahydro-1-naphthyl)phenoxy] propionic acid; Su-13,437), a potent hypolipidemic hepatic peroxisome proliferator, was fed to male F344 rats at a dietary concentration of o.1% until the end of the experiment at 25 months. Between 18 and 25 months, 12 of 15 rats (80%) developed tumors. Approximately 73% (11/15) developed hepatocellular carcinomas, and 10% (3/15) developed pancreatic acinar cell tumors, including 1 metastasizing carcinoma. The hepatocellular carcinomas as well as the acinar cell carcinoma of the pancreas were transplantable successfully through 6 generations.

Hepatocellular carcinomas in acatalasemic mice treated with nafenopin, a hypolipidemic peroxisome proliferator.

The effects of long-term administration of nafenopin, a potent hypolipidemic drug with marked hepatomegalic and peroxisome-proliferative properties, were studied in wild-type (Csa strain) and acatalasemic (Csb strain) mice. Nafenopin was administered in the diet at a concentration of 0.1% during the first 12 months and then at 0.05% until the termination of the experiment at 20 months. By 56 weeks, 100% mortality occurred in both male and female wild-type mice, whereas the mortality rate in acatalasemic mice was approximately 50%. Between 18 and 20 months of the experiment, 9 of 9 male and 12 of 12 female acatalasemic mice that survived chronic nafenopin treatment developed hepatocellular carcinomas, some of which metastasized to the lungs. None of the 15 male and 15 female acatalasemic controls developed liver cancers. Numerous peroxisomes were seen in the lung metastases of these hepatocellular carcinomas on electron microscopic examination; in contrast the number of peroxisomes in primary liver tumor cells varied considerably. The hepatocarcinogenicity of nafenopin strongly suggests the need for long-term studies with other hypolipidemic drugs that cause hepatomegaly and peroxisome proliferation to clarify the role, if any, of peroxisome proliferation in liver carcinogenesis.