Mechanism of expression and function of drug transporters in endotoxemia

首先，研究了内毒素（ET）对小鼠肝性乳腺癌抵抗蛋白（Bcrp）功能及表达的影响。体内清除率实验显示，注射ET后24 h，米托蒽醌的胆道清除率（CL_<BILE>）明显降低。Western blot和免疫荧光分析显示，注射ET后24 h肝脏Bcrp蛋白水平降低，ET显著诱导细胞因子IL-6和IL-1β过量产生。IL-6预处理可显著降低米托蒽醌的CL_<BILE>。注射IL-6（5万u /只）显著下调肝脏Bcrp水平。这些发现表明，ET通过降低肝脏Bcrp的表达来减少Bcrp介导的米托蒽醌的肝胆排泄，这可能是由于IL-6水平升高。其次，为了阐明et诱导的有机阴离子转运能力的变化，我们在内毒素中毒大鼠中研究了肾有机阴离子转运蛋白1 （Oat1）和Oat3的底物PAH的GFR和肾小管分泌清除率。注射ET后72h， Oat1和Oat3 mRNA表达降低，并恢复到对照水平。提示内毒素中毒大鼠肾小管分泌对PAH清除率的降低与肾脏Oat1和Oat3 mRNA水平的降低有关，且这种变化是短暂的、恢复时间依赖性的。

Firstly, the effect of endotoxin (ET) on the function and expression of hepatic breast cancer resistance protein (Bcrp) was investigated in mice. In vivo clearance experiments showed that the biliary clearance (CL_<BILE>) of mitoxantrone was significantly decreased 24 h after ET injection. Both Western blot and immunofluorescence analyses also revealed that the protein levels of hepatic Bcrp were decreased 24 h after injection of ET. ET significantly induced the overproduction of the cytokines IL-6 and IL-1β. Pretreatment with IL-6 significantly decreased the CL_<BILE> of mitoxantrone. Hepatic Bcrp was significantly down-regulated by injection of IL-6 (50,000U/mouse). These findings suggest that ET reduces Bcrp-mediated hepatobiliary excretion of mitoxantrone by decreasing the expression of hepatic Bcrp, which is likely due to increased IL-6 levels. Secondly, to clarify ET-induced changes in organic anion transport ability, GFR and renal tubular secretion clearance of PAH which is a substrate for renal organic anion transporter 1 (Oat1) and Oat3 were investigated in endotoxemic rats. The expression of Oat1 and Oat3 mRNA was decreased, and the expression returned to control levels after 72 h after injection of ET. These findings suggest that the decreased mRNA levels of renal Oat1 and Oat3 are involved in the decreased renal tubular secretion clearance of PAH in endotoxemic rats and that these changes are transient and recovered time-dependently.