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Hepatocellular Carcinomas in Acatalasemic Mice Treated with Nafenopin, a Hypolipidemic Peroxisome Proliferator¹

Department of Pathology and Oncology, University of Kansas Medical Center, College of Health Sciences and Hospital, Kansas City, Kansas 66103

The effects of long-term administration of nafenopin, a potent hypolipidemic drug with marked hepatomegalic and peroxisome-proliferative properties, were studied in wildtype (Cs^a strain) and acatalasemic (Cs^b 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.

¹ Supported by USPHS Grant GM-15956.

Received 10/28/75. Accepted 12/17/75.

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