Utili R, Adinolfi L E, Gaeta G B, Tripodi M F, Alvaro D
Digestion. 1987;36(2):74-80. doi: 10.1159/000199402.
Induction of endotoxin tolerance may cause resistance not only to endotoxin itself but also to the hepatotoxic effects of other membrane-active agents. To further study this effect, we tested whether endotoxin tolerance could ameliorate the adverse effects of taurolithocholate (TLCA) which causes cholestasis by altering liver plasma membrane organization. Isolated perfused rat livers from endotoxin-tolerant rats had a lower basal bile flow than control livers. However, a bolus addition of TLCA at 3 X 10(-5) or 5 X 10(-5) M in the perfusate caused a marked and prolonged decrease of bile flow in controls, but only a transient and significantly less pronounced diminution of bile flow in endotoxin-tolerant livers. Likewise, TLCA caused a significantly lower alteration of hepatocyte membrane permeability, as measured by sucrose permeability studies, in endotoxin-tolerant livers than in controls. Analysis of bile acid composition of bile from endotoxin-tolerant livers demonstrated that they excreted greater amounts of total bile acids, in particular TLCA and taurocholate, than controls. These results demonstrated a protective effect of endotoxin-tolerance against TLCA toxicity which may result from an altered interaction of TLCA with liver membranes and an increased clearance of TLCA.
内毒素耐受的诱导可能不仅导致对内毒素本身的抵抗，还导致对其他膜活性药物肝毒性作用的抵抗。为了进一步研究这种效应，我们测试了内毒素耐受是否可以改善牛磺石胆酸（TLCA）的不良反应，TLCA 通过改变肝细胞膜组织导致胆汁淤积。来自内毒素耐受大鼠的离体灌注肝脏的基础胆汁流量低于对照肝脏。然而，在灌注液中以3×10⁻⁵或5×10⁻⁵M的剂量推注TLCA会导致对照肝脏中的胆汁流量显著且持续下降，但在内毒素耐受的肝脏中仅导致胆汁流量短暂且明显较小的减少。同样，通过蔗糖通透性研究测量，TLCA 在内毒素耐受的肝脏中引起的肝细胞膜通透性变化明显低于对照肝脏。对内毒素耐受肝脏胆汁中胆汁酸组成的分析表明，它们排泄的总胆汁酸量，特别是 TLCA 和牛磺胆酸盐，比对照肝脏更多。这些结果证明了内毒素耐受对 TLCA 毒性的保护作用，这可能是由于 TLCA 与肝细胞膜的相互作用改变以及 TLCA 的清除增加所致。
