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Toxicologic Pathology
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*RIFABUTIN
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Journal Article

Multinucleated Hepatocytes Induced by Rifabutin in Rats

Giovanna Scampini

R&D/Farmitalia Carlo Erba, Via Giovanni XXIII, 23, Nerviano, Italy

Alberto Nava

R&D/Farmitalia Carlo Erba, Via Giovanni XXIII, 23, Nerviano, Italy

Arthur John Newman

P.O. Box 22, Liskeard, Cornwall PL14 6YA, United Kingdom

Paola Delia Torre

R&D/Farmitalia Carlo Erba, Via Giovanni XXIII, 23, Nerviano, Italy

Guy Mazuéa

R&D/Farmitalia Carlo Erba, Via Giovanni XXIII, 23, Nerviano, Italy

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 (12 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.

Key Words: Liver • antibiotic

Toxicologic Pathology, Vol. 21, No. 4, 369-376 (1993)
DOI: 10.1177/019262339302100404
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