Stone J L, Braunstein J B, Beaty T M, Sanders R A, Watkins J B
Medical Sciences Program, Indiana University School of Medicine, Bloomington 47405-4201, USA.
J Pharmacol Exp Ther. 1997 Apr;281(1):412-9.
Divergent opinions regarding the effect of streptozotocin- (STZ) induced diabetes on bile flow rate may be due to the differing lengths of time after STZ administration at which bile flow was measured. Also, the biliary excretion of bile acids can influence the canalicular transport of several organic anions. Therefore, the hepatic clearance of the bile acid-dependent organic anion rose bengal was studied over a 30-day period in STZ-induced insulin-dependent Sprague-Dawley diabetic rats with elevated bile acid pools and in fatty noninsulin-dependent diabetic and lean Wistar rats. Excretion of total bile acids and rose bengal was higher in diabetic rats than in Sprague-Dawley control or lean or fatty Wistar rats. Depletion of bile acids for 10 hr in the 30-day STZ rat prevented the increased excretion of rose bengal. Bile flow rates in fatty and lean Wistar rats were similar to that in Sprague-Dawley controls. Increased bile acid excretion 7 and 14 days after STZ was not accompanied by the expected significant increase in bile flow, reflecting decreased bile acid-independent bile flow, regardless of method of calculation of bile flow (per g liver or per kg body weight). By 30 days, there were significant increases in bile acid excretion and bile flow. The increased clearance of rose bengal 7 days after STZ indicates that pathophysiological changes in the hepatocyte begin soon after the initiation of diabetes. Studies of taurocholate uptake into liver plasma membrane vesicles indicated that the maximal velocity of transport across the basolateral membrane was increased with no change in Km. This change was not observed in vesicles from insulin-treated diabetic rats. Therefore, studies employing STZ need to allow time for STZ toxicity to be overcome and for the pathology of diabetes to become established, to accurately reflect the diabetic condition.
关于链脲佐菌素（STZ）诱导的糖尿病对胆汁流速的影响存在不同观点，这可能是由于在STZ给药后测量胆汁流速的时间长度不同所致。此外，胆汁酸的胆汁排泄可影响几种有机阴离子的胆小管转运。因此，在胆汁酸池升高的STZ诱导的胰岛素依赖型斯普拉格-道利糖尿病大鼠以及脂肪型非胰岛素依赖型糖尿病大鼠和瘦型Wistar大鼠中，对胆汁酸依赖性有机阴离子玫瑰红的肝脏清除进行了为期30天的研究。糖尿病大鼠中总胆汁酸和玫瑰红的排泄高于斯普拉格-道利对照大鼠或瘦型或脂肪型Wistar大鼠。在30天的STZ大鼠中，胆汁酸耗竭10小时可防止玫瑰红排泄增加。脂肪型和瘦型Wistar大鼠的胆汁流速与斯普拉格-道利对照大鼠相似。STZ给药后7天和14天胆汁酸排泄增加，但未伴随预期的胆汁流速显著增加，这反映了胆汁酸非依赖性胆汁流速降低，无论胆汁流速的计算方法是每克肝脏还是每千克体重。到30天时，胆汁酸排泄和胆汁流速显著增加。STZ给药后7天玫瑰红清除增加表明糖尿病开始后不久肝细胞就开始出现病理生理变化。对牛磺胆酸盐摄取到肝质膜囊泡中的研究表明，跨基底外侧膜转运的最大速度增加，而Km无变化。在胰岛素治疗的糖尿病大鼠的囊泡中未观察到这种变化。因此，采用STZ的研究需要留出时间来克服STZ毒性并使糖尿病病理形成，以准确反映糖尿病状况。
