Gaeta G B, Adinolfi L E, Utili R, Tripodi M F, Abernathy C O
Life Sci. 1986 Aug 4;39(5):453-60. doi: 10.1016/0024-3205(86)90525-4.
The possibility that endotoxin pretreatment could prevent the hepatotoxic effects of erythromycin estolate (EE) was investigated using the isolated perfused rat liver. The addition of E. coli endotoxin (25 micrograms/ml) to the perfusate, 30 min prior to EE administration at 150 or 200 microM, significantly ameliorated the decreases in bile and perfusate flow caused by either concentrations of the drug in control liver preparations. This phenomenon was also studied using liver isolated from rats pretreated in vivo with endotoxin for three days. In these preparations, EE at both concentrations did not alter bile flow and caused reductions of perfusate flow which were far less than those observed in untreated control livers. Furthermore, in livers from endotoxin-treated rats EE induced less reduction of bile acid excretion and, at 150 microM, it did not increase the bile to perfusate ratio of sucrose seen in control preparations after the drug, which may be an expression of altered hepatocytic membrane permeability. Since it is known that both endotoxin and EE interact with membranes, it is suggested that the "protective" effects of endotoxin may occur at the membrane level.
利用离体灌注大鼠肝脏，研究内毒素预处理能否预防依托红霉素（EE）的肝毒性作用。在给予150或200微摩尔EE前30分钟，向灌流液中加入大肠杆菌内毒素（25微克/毫升），可显著改善两种浓度药物在对照肝制剂中所引起的胆汁和灌流液流量降低。还利用从体内用内毒素预处理三天的大鼠分离的肝脏研究了这一现象。在这些制剂中，两种浓度的EE均未改变胆汁流量，且引起的灌流液流量降低远小于未处理对照肝脏中观察到的降低幅度。此外，在内毒素处理大鼠的肝脏中，EE引起的胆汁酸排泄减少较少，在150微摩尔时，它不会增加药物处理后对照制剂中蔗糖的胆汁与灌流液比值，这可能是肝细胞细胞膜通透性改变的一种表现。由于已知内毒素和EE均与细胞膜相互作用，因此提示内毒素的“保护”作用可能发生在膜水平。
