Characterization of Multinuclear Hepatocytes Induced in Rats by Mitemcinal (GM-611), an Erythromycin Derivative
Characterization of Multinuclear Hepatocytes Induced in Rats by Mitemcinal (GM-611), an Erythromycin Derivative
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DOI：
10.1177/0192623308322307
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发表时间：
2008-10-01
影响因子：
1.5
通讯作者：
Wanibuchi, Hideki
中科院分区：
文献类型：
--
作者：
Hayashi, Shuji;Fujii, Etsuko;Wanibuchi, Hideki
丝裂霉素是一种具有胃动素激动素作用的红霉素衍生物，作为胃肠运动激动剂而开发。本文报道了用细胞离心法和5-溴-2‘-脱氧尿嘧啶核苷累积标记相结合的方法对丝裂原诱导的多核肝细胞(MNH)的形态特征和MNH形成机制的研究结果。仅在亚慢性研究的高剂量组大鼠中观察到MNHs，雌性大鼠发病率较高，停药28天后可逆性较高，但在狗身上未观察到MNHs。在慢性研究中，发病率随剂量增加而增加。病理组织学上，MNHs多见于小叶中心区，无核异型性或有丝分裂像。在细胞动力学研究中，MNHs的标记模式包括核的全阳性、全阴性和混合标记模式。全阴性模式表明，这些细胞是由未分裂细胞融合而成。目前的结果表明，细胞动力学方法有效地证明了丝裂原诱导的肝细胞融合的机制，药物诱导的有丝分裂障碍不参与丝裂原诱导的MNHs的多核。
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.