Howell J H, Marsh M E, Thiel E S, Holzbach R T
Biochim Biophys Acta. 1983 Aug 29;753(1):32-9. doi: 10.1016/0005-2760(83)90094-2.
The prairie dog is a useful experimental animal model for studies of cholesterol gallstone pathogenesis. The unique susceptibility to rapid induction of gallstones solely by feeding of a 1.2% cholesterol diet in this species could result from low levels of hepatic cholesterol 7 alpha-hydroxylase. With optimal assay conditions in hepatic microsomes, a basal specific activity of about 25 pmol/min per g protein was found. Administration of diets containing 1.2% cholesterol or 5% cholestyramine caused hydroxylase levels to increase 60 and 250%, respectively. This response pattern is similar to that observed in other species under the same conditions, indicating that abnormally low basal or inappropriately unresponsive hydroxylase levels are not susceptibility factors unique to this model. With optimal assay conditions for hydroxymethylglutaryl-CoA reductase, a Km of 32.5 microM (S-HMG-CoA) and basal specific activities of between 60 and 175 pmol/min per mg protein were found. Following feeding of either sodium chenodeoxycholate or sodium cholate, in reasonable pharmacologic doses, no suppression of hydroxylase and reductase levels was found. These findings undermine the widely held view that the therapeutic effect of oral chenodeoxycholate in man for cholesterol gallstone dissolution is directly mediated by suppression of the activities of these enzymes.
草原犬鼠是研究胆固醇性胆结石发病机制的一种有用的实验动物模型。该物种仅通过喂食1.2%胆固醇饮食就能快速诱发胆结石，其独特的易感性可能是由于肝胆固醇7α-羟化酶水平较低所致。在肝微粒体的最佳检测条件下，发现基础比活性约为每克蛋白质25 pmol/分钟。给予含1.2%胆固醇或5%消胆胺的饮食会使羟化酶水平分别增加60%和250%。这种反应模式与在相同条件下其他物种中观察到的相似，表明基础水平异常低或反应不当的羟化酶水平不是该模型特有的易感性因素。在羟甲基戊二酰辅酶A还原酶的最佳检测条件下，发现Km为32.5 μM（S-HMG-CoA），基础比活性为每毫克蛋白质60至175 pmol/分钟。以合理的药理剂量喂食鹅去氧胆酸钠或胆酸钠后，未发现羟化酶和还原酶水平受到抑制。这些发现削弱了人们普遍持有的观点，即口服鹅去氧胆酸对人体胆固醇性胆结石溶解的治疗作用是通过抑制这些酶的活性直接介导的。
