Reihnér E, Björkhem I, Angelin B, Ewerth S, Einarsson K
Department of Surgery, Karolinska Institutet, Huddinge University Hospital, Sweden.
Gastroenterology. 1989 Dec;97(6):1498-505. doi: 10.1016/0016-5085(89)90395-8.
The present work tested the hypothesis that portal venous bile acids regulate the activity of the cholesterol 7 alpha-hydroxylase and studied the influence of hepatic microsomal free cholesterol concentration on the enzyme activity. Operative liver biopsies and samples of portal venous blood were obtained from a total of 61 patients with gallstones who were undergoing cholecystectomy. Fifteen of the patients were treated with cholestyramine (16 g/day) for 2-3 wk before operation and 23 patients with chenodeoxycholic acid (15 mg/kg.day) or ursodeoxycholic acid (15 mg/kg.day) for 3-4 wk before operation. Highly accurate methods based on isotope dilution-mass spectrometry were used for assay of the cholesterol 7 alpha-hydroxylase activity, the concentration of free cholesterol in the microsomes, and the levels of individual bile acids in portal venous blood. Cholestyramine treatment increased the cholesterol 7 alpha-hydroxylase activity about sixfold, from 7.6 +/- 1.1 (mean +/- SEM) to 45.7 +/- 6.7 pmol/min.mg protein. Administration of chenodeoxycholic acid reduced the enzyme activity considerably to 1.0 +/- 0.3 pmol/min.mg protein, whereas ursodeoxycholic acid did not significantly affect the enzyme activity (7.9 +/- 2.2 pmol/min.mg protein). The concentration of microsomal free cholesterol remained essentially unchanged in spite of a 45-fold variation in enzyme activity. There was a negative correlation between the absolute as well as the relative concentration of chenodeoxycholic acid in portal blood and the activity of the cholesterol 7 alpha-hydroxylase, whereas there was no correlation between the total concentration of bile acids and the enzyme activity. It is concluded that the composition of individual bile acids may be more important than the total concentration of bile acids in the portal vein for the regulation of the cholesterol 7 alpha-hydroxylase activity in humans. It is further concluded that chenodeoxycholic acid is a considerably stronger suppressor of bile acid synthesis than ursodeoxycholic acid.
本研究检验了门静脉胆汁酸调节胆固醇7α-羟化酶活性这一假说，并研究了肝微粒体游离胆固醇浓度对该酶活性的影响。从总共61例接受胆囊切除术的胆结石患者身上获取手术肝活检组织和门静脉血样本。其中15例患者在手术前接受消胆胺（16克/天）治疗2 - 3周，23例患者在手术前接受鹅去氧胆酸（15毫克/千克·天）或熊去氧胆酸（15毫克/千克·天）治疗3 - 4周。采用基于同位素稀释-质谱分析法的高精度方法来测定胆固醇7α-羟化酶活性、微粒体中游离胆固醇的浓度以及门静脉血中各胆汁酸的水平。消胆胺治疗使胆固醇7α-羟化酶活性增加了约6倍，从7.6±1.1（平均值±标准误）增至45.7±6.7皮摩尔/分钟·毫克蛋白。给予鹅去氧胆酸使该酶活性大幅降低至1.0±0.3皮摩尔/分钟·毫克蛋白，而熊去氧胆酸对酶活性无显著影响（7.9±2.2皮摩尔/分钟·毫克蛋白）。尽管酶活性有45倍的变化，但微粒体游离胆固醇浓度基本保持不变。门静脉中鹅去氧胆酸的绝对浓度和相对浓度与胆固醇7α-羟化酶活性之间呈负相关，而胆汁酸的总浓度与酶活性之间无相关性。得出的结论是，对于人类胆固醇7α-羟化酶活性的调节，门静脉中各胆汁酸的组成可能比胆汁酸的总浓度更为重要。进一步得出的结论是，鹅去氧胆酸对胆汁酸合成的抑制作用比熊去氧胆酸强得多。
