Kossor D C, Goldstein R S, Ngo W, DeNicola D B, Leonard T B, Dulik D M, Meunier P C
Department of Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Fundam Appl Toxicol. 1995 Jun;26(1):51-62. doi: 10.1006/faat.1995.1074.
These studies were designed to evaluate the importance of bile duct obstruction in the pathogenesis of alpha-naphthylisothiocyanate (ANIT)-induced biliary epithelial cell (BEC) hyperplasia in rats. Hepatobiliary function and morphology were evaluated in adult male Sprague-Dawley rats 16, 24, 48, 72, 120, and 168 hr after a single oral dose of ANIT (0, 25, 75, or 150 mg/kg). After 75 or 150 mg/kg ANIT, multifocal bile duct obstruction was observed at 48 and 72 hr and preceded BEC hyperplasia which occurred at 120 and 168 hr. BEC proliferation, reflected by 5-bromo-2'-deoxyuridine (BrdU) incorporation, occurred at doses and at time points coinciding with BEC necrosis and/or bile duct obstruction. In contrast, 25 mg/kg ANIT produced minimal BEC damage and no evidence of bile duct obstruction or BEC hyperplasia. In a separate experiment, BEC proliferation was evaluated following bile duct ligation or ANIT treatment (150 mg/kg). The onset and peak of BEC proliferation occurred 24 and 48 hr, respectively, following bile duct obstruction resulting from either ligation or ANIT treatment. Furthermore, BEC proliferation occurred at all levels of the biliary tree in both bile duct-ligated and ANIT-treated rats. These data indicate that (a) dose-response curves for ANIT-induced bile duct obstruction and BEC hyperplasia are similar; (b) ANIT-induced BEC proliferation and bile duct obstruction precedes BEC hyperplasia; (c) BEC proliferation occurred at doses/timepoints associated with BEC damage and bile duct obstruction; and (d) once ANIT-induced bile duct obstruction occurs, the spatial and temporal aspects of BEC proliferation are comparable to those following biliary obstruction induced by bile duct ligation. Collectively, these data suggest that ANIT-induced BEC hyperplasia is secondary to intrahepatic bile duct obstruction.
这些研究旨在评估胆管梗阻在α-萘基异硫氰酸盐（ANIT）诱导的大鼠胆管上皮细胞（BEC）增生发病机制中的重要性。在成年雄性Sprague-Dawley大鼠单次口服ANIT（0、25、75或150mg/kg）后16、24、48、72、120和168小时，对其肝胆功能和形态进行评估。给予75或150mg/kg ANIT后，在48和72小时观察到多灶性胆管梗阻，随后在120和168小时出现BEC增生。以5-溴-2'-脱氧尿苷（BrdU）掺入反映的BEC增殖，在与BEC坏死和/或胆管梗阻一致的剂量和时间点出现。相比之下，25mg/kg ANIT产生的BEC损伤最小，没有胆管梗阻或BEC增生的证据。在另一项实验中，在胆管结扎或ANIT治疗（150mg/kg）后评估BEC增殖。胆管结扎或ANIT治疗导致胆管梗阻后，BEC增殖的起始和峰值分别出现在24和48小时。此外，在胆管结扎和ANIT治疗的大鼠中，BEC增殖发生在胆管树的所有水平。这些数据表明：（a）ANIT诱导的胆管梗阻和BEC增生的剂量反应曲线相似；（b）ANIT诱导的BEC增殖和胆管梗阻先于BEC增生；（c）BEC增殖发生在与BEC损伤和胆管梗阻相关的剂量/时间点；（d）一旦ANIT诱导的胆管梗阻发生，BEC增殖的空间和时间方面与胆管结扎诱导的胆管梗阻后的情况相当。总体而言，这些数据表明ANIT诱导的BEC增生继发于肝内胆管梗阻。
