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Characterization of Multinuclear Hepatocytes Induced in Rats by Mitemcinal (GM-611), an Erythromycin Derivative

Shuji Hayashi¹, Etsuko Fujii¹, Atsuhiko Kato¹, Kazuya Kimura¹, Keiji Mizoguchi¹, Masami Suzuki¹, Tetsuro Sugimoto¹, Hisanori Takanashi¹, Zen Itoh², Satoshi mura³ and Hideki Wanibuchi⁴

¹ Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan
² Gunma University, Maebashi, Gunma, Japan
³ The Kitasato Institute, Minato-ku, Tokyo, Japan
⁴ Osaka City University Medical School, Abeno-ku, Osaka, Japan

Correspondence: Shuji Hayashi, Safety Assessment Department, Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., LTD. 1–135 Komakado, Gotemba, Shizuoka 412–8513, Japan; E-mail:hayashisuj{at}chugai-pharm.co.jp

Mitemcinal is an erythromycin derivative with motilin agonistic action, developed as a gastrointestinal motor-activating agent. The characteristics of mitemcinal-induced multinuclear hepatocytes (MNHs, hepatocytes with three or more nuclei per cell) from detailed morphological observations together with the results of a study on the mechanisms of MNH formation by combining cytocentrifuge preparations with 5-bromo-2’-deoxyuridine cumulative labeling are reported. MNHs were observed only in rats in the high-dose groups of the subchronic study, with a higher incidence in females and reversibility after twenty-eight days of drug withdrawal, but not observed in dogs. In the chronic study, the incidence increased relative to the dose. Histopathologically, MNHs were preferentially observed in the centrilobular zone, without nuclear atypia or mitotic figures. In the cell kinetic study, the labeling pattern of MNHs included all-positive, all-negative, and mixed labeling patterns of nuclei. The all-negative pattern indicated that the cells were formed by fusion of nondividing cells. The current results indicate that the cell kinetic approach effectively demonstrated the mechanism of mitemcinal-induced MNHs as fusion of hepatocytes and that drug-induced disturbance of mitosis is not involved in the multinucleation of MNHs by mitemcinal.

Key Words: bromodeoxyuridine • cell kinetics • cytocentrifuge preparations • mitemcinal • multinuclear hepatocyte • nuclearity • rats

Abbreviations: BrdU, 5-bromo-2’-deoxyuridine • MNH, multinuclear hepatocyte

This version was published on October 1, 2008

Toxicologic Pathology, Vol. 36, No. 6, 858-865 (2008)
DOI: 10.1177/0192623308322307


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