Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
Chem Biodivers. 2009 Nov;6(11):1943-59. doi: 10.1002/cbdv.200900053.
Hepatic ABC efflux transporters control the cellular uptake (in basolateral membranes) and excretion (in apical membranes) of many substrates. Since type-1 diabetes mellitus (T1DM) is associated with altered hepatobiliary excretion of many endogenous and exogenous substances, we examined key hepatic ABC transporters and levels of the endogenous substrate glutathione in rats with acute streptozotocin-induced T1DM. Renal transporters and inflammatory markers were also examined. Abcb1, Abcc1-4, and Abcg2 were measured using qRT-PCR. Glutathione was measured in liver tissue, plasma, and urine. Inflammatory markers, including C-reactive protein (CRP), were measured in plasma via ELISA. In diabetic rats, Abcb1a, Abcc2, and Abcg2 (apical) were decreased, while Abcc4 (basolateral) was increased. Abcb1a and Abcc2 inversely correlated with plasma CRP. Diabetic and control rats exhibited similar hepatic glutathione, but levels in diabetic plasma were lower. When standardized to urinary output, diabetic rats excreted 6.7-fold more glutathione in urine than controls. Renal transporter levels were normal in diabetic rats. Results show apical transporters involved in hepatobiliary excretion are downregulated in T1DM, possibly through an inflammation-mediated process. Findings suggest that there may be a vectorial shift from hepatic to renal excretion for some substrates in T1DM.
肝脏 ABC 外排转运体控制许多底物的细胞摄取（在基底外侧膜）和排泄（在顶膜）。由于 1 型糖尿病（T1DM）与许多内源性和外源性物质的肝胆排泄改变有关，我们检查了急性链脲佐菌素诱导的 T1DM 大鼠中的关键肝脏 ABC 转运体和内源性底物谷胱甘肽的水平。还检查了肾脏转运体和炎症标志物。使用 qRT-PCR 测量 Abcb1、Abcc1-4 和 Abcg2。在肝组织、血浆和尿液中测量谷胱甘肽。通过 ELISA 在血浆中测量炎症标志物，包括 C 反应蛋白（CRP）。在糖尿病大鼠中，Abcb1a、Abcc2 和 Abcg2（顶膜）减少，而 Abcc4（基底外侧膜）增加。Abcb1a 和 Abcc2 与血浆 CRP 呈负相关。糖尿病和对照组大鼠的肝内谷胱甘肽相似，但糖尿病组血浆中的水平较低。标准化为尿排量时，糖尿病大鼠尿液中排泄的谷胱甘肽比对照组多 6.7 倍。糖尿病大鼠的肾脏转运体水平正常。结果表明，T1DM 中涉及肝胆排泄的顶膜转运体下调，可能通过炎症介导的过程。研究结果表明，T1DM 中某些底物可能从肝脏向肾脏排泄的方向发生了变化。
