Multinucleated Hepatocytes Induced by Rifabutin in Rats

Abstract

AESTRAC~Rifabutin is an antibiotic of the rifamycin class, which is particularly active against mycobacteria, including those that occur in AIDS patients. Because clinical use will include long-term therapy, an extensive battery of long-term toxicity studies was carried out by the oral route, including carcinogenicity studies. An interesting feature was the occurrence of multinucleated hepatocytes (MNHs) in the rat. In some instances, as many as 25 nuclei occurred in a single cell. Light microscopy revealed a large hepatocyte with normal eosinophilic staining. The multiple nuclei stained like those present in the surrounding normal cells. Electron microscopy showed no abnormalities of the nuclei and no cell membranes within the cytoplasm. The customary organelles were present. MNHs were dose-and sex-related, starting from 10 mg/kg/day and being more evident in males. They began to appear after 5 wk of treatment and persisted over long periods of recovery ( I 2 mo), without showing any tendency for cell proliferation. The life-span of MNHs was similar to that of normal hepatocytes. MNHs were present in the carcinogenicity study, but there was no increase in liver tumors.MNHs did not occur in mice or monkeys treated with rifabutin, nor did they occur in response to treatment with rifampin. The effect appears to be specific to the rat.Keywords. Liver; antibiotic . INTRODUC~ION Rifabutin is an antibiotic of the rifamycin class, which is particularly active against mycobacteria including those that occur in AIDS patients. Because clinical use will include long-term therapy, an extensive battery of long-term toxicity studies was carried out by the oral route, including carcinogenicity studies.At the beginning of the customary safety experiments in the rat, the presence in the liver of multinucleated hepatocytes (MNHs) was discovered. In this article, we report the details of our extensive investigation of the phenomenon. MATERIALS AND MITHODSThe customary toxicity studies for safety evaluation were carried out in rats, mice, and monkeys.The majority of the studies, particularly those of rats, were carried out at Farmitalia Carlo Erba, whereas a proportion of those in mice and monkeys were performed under the supervision of Farmitalia Carlo Erba in independent contract laboratories. Materials, methods, and results are to be reported separately (4). The details of the studies are given in Table I. In these, the customary investigations were performed including the recording of body weight, clinical signs, ophthalmoscopy, food and water consumption, hematology, and clinical biochemistry. At termination, a full necropsy was carried out, the customary organs were weighed, and pumerous tissues were examined for histopathologYFor these studies, rifabutin of pharmaceutical grade and 96.48% purity was obtained from the Department , . .... of R&D/Galenics, Farmitalia (Milan) and, similarly, rifampin of 94.6% purity was supplied by SPA (Milan).Because MNHs were seen to occur in the liver of rats with evidence of a dose-related e...

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