MULTINUCLEATED HEPATOCYTES INDUCED BY RIFABUTIN IN RATS

Rifabutin is an antibiotic of the rifamycin class, which is particular ly active against mycobacteria, including those that occur in AIDS pat ients. Because clinical use will include long-term therapy, an extensi ve battery of long-term toxicity studies was carried out by the oral r oute, including carcinogenicity studies. An interesting feature was th e occurrence of multinucleated hepatocytes (MNHs) in the rat. In some instances, as many as 25 nuclei occurred in a single cell. Light micro scopy revealed a large hepatocyte with normal eosinophilic staining. T he multiple nuclei stained like those present in the surrounding norma l 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 tr eatment and persisted over long periods of recovery (12 mo), without s howing any tendency for cell proliferation. The life-span of MNHs was similar to that of normal hepatocytes. MNHs were present in the carcin ogenicity study, but there was no increase in liver tumors. MNHs did n ot occur in mice or monkeys treated with rifabutin, nor did they occur in response to treatment with rifampin. The effect appears to be spec ific to the rat.