title: Characterization of multinuclear hepatocytes induced in rats by mitemcinal (GM-611), an erythromycin derivative.
abstract: 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.
authors.affiliation: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. hayashisuj@chugai-pharm.co.jp
authors.forename: Shuji
authors.initials: S
authors.lastname: Hayashi
authors.forename: Etsuko
authors.initials: E
authors.lastname: Fujii
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kato
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kimura
authors.forename: Keiji
authors.initials: K
authors.lastname: Mizoguchi
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Hisanori
authors.initials: H
authors.lastname: Takanashi
authors.forename: Zen
authors.initials: Z
authors.lastname: Itoh
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D048430:Cell Shape / Q000187:drug effects; D004285:Dogs; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure*; D007700:Kinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004917:Erythromycin; C103741:mitemcinal; D001973:Bromodeoxyuridine