West Kristy L, Ramjiganesh Tripurasundari, Roy Suheeta, Keller Bradley T, Fernandez Maria Luz
Department of Nutritional Sciences, University of Connecticut, Storrs 06269, USA.
J Pharmacol Exp Ther. 2002 Oct;303(1):293-9. doi: 10.1124/jpet.102.038711.
Male Hartley guinea pigs (10/group) were assigned either to a control diet (no drug treatment) or to diets containing 0.4, 2.2, or 7.3 mg/day of an ileal apical sodium-codependent bile acid transporter (ASBT) inhibitor, 1-[4-[4[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2] octane methanesulfonate (SC-435). Based on food consumption, guinea pigs received 0, 0.8, 3.7, or 13.4 mg/kg/day of the ASBT inhibitor. The amount of cholesterol in the four diets was maintained at 0.17%, equivalent to 1200 mg/day in the human situation. Guinea pigs treated with 13.4 mg/kg/day SC-435 had 41% lower total cholesterol and 44% lower low-density lipoprotein (LDL)-cholesterol concentrations compared with control (P < 0.01), whereas no significant differences were observed with either of the lower doses of SC-435. Hepatic cholesterol esters were significantly reduced by 43, 56, and 70% in guinea pigs fed 0.8, 3.7, and 13.4 mg/kg/day of the ASBT inhibitor, respectively (P < 0.01). In addition, the highest dose of the inhibitor resulted in a 42% increase in the number of very low-density lipoprotein (VLDL) triacylglycerol molecules and a larger VLDL diameter compared with controls (P < 0.05). Acyl-CoA cholesterol/acyltransferase activity was 30% lower with the highest dose treatment, whereas cholesterol 7alpha-hydroxylase, the regulatory enzyme of bile acid synthesis, was 30% higher with the highest ASBT inhibitor dose (P < 0.05). Furthermore, bile acid excretion increased 2-fold with the highest dose of SC-435 compared with the control group (P < 0.05). These results suggest that the reduction in total and LDL-cholesterol concentrations by the ASBT inhibitor is a result of alterations in hepatic cholesterol metabolism due to modifications in the enterohepatic circulation of bile acids.
将雄性Hartley豚鼠（每组10只）分为两组，一组给予对照饮食（无药物治疗），另一组给予含0.4、2.2或7.3毫克/天回肠顶端钠依赖性胆汁酸转运体（ASBT）抑制剂1-[4-[4[(4R,5R)-3,3-二丁基-7-(二甲氨基)-2,3,4,5-四氢-4-羟基-1,1-二氧化-1-苯并硫氮杂䓬-5-基]苯氧基]丁基]-4-氮杂-1-氮鎓双环[2.2.2]辛烷甲磺酸盐（SC-435）的饮食。根据食物摄入量，豚鼠接受0、0.8、3.7或13.4毫克/千克/天的ASBT抑制剂。四种饮食中的胆固醇含量维持在0.17%，相当于人类情况下的1200毫克/天。与对照组相比，接受13.4毫克/千克/天SC-435治疗的豚鼠总胆固醇降低41%，低密度脂蛋白（LDL）胆固醇浓度降低44%（P<0.01），而较低剂量的SC-435未观察到显著差异。分别给予0.8、3.7和13.4毫克/千克/天ASBT抑制剂的豚鼠肝脏胆固醇酯显著降低43%、56%和70%（P<0.01）。此外，与对照组相比，最高剂量的抑制剂导致极低密度脂蛋白（VLDL）三酰甘油分子数量增加42%，VLDL直径增大（P<0.05）。最高剂量治疗时酰基辅酶A胆固醇/酰基转移酶活性降低30%，而胆汁酸合成的调节酶胆固醇7α-羟化酶在ASBT抑制剂最高剂量时升高30%（P<0.05）。此外，与对照组相比，最高剂量的SC-435使胆汁酸排泄增加了2倍（P<0.05）。这些结果表明，ASBT抑制剂降低总胆固醇和LDL胆固醇浓度是由于胆汁酸肠肝循环改变导致肝脏胆固醇代谢改变的结果。
