Goldman M, Vlahcevic Z R, Schwartz C C, Gustafsson J, Swell L
Hepatology. 1982 Jan-Feb;2(1):59-66. doi: 10.1002/hep.1840020110.
In order to evaluate more definitively the observed aberrations in the synthesis of cholic and chenodeoxycholic acids in patients with advanced cirrhosis, two bile acid biosynthesis pathways were examined by determining the efficiency of conversion of [3H]7 alpha-hydroxycholesterol and [3H] 26-hydroxycholesterol to primary bile acids. Bile acid kinetics were determined by administration of [14C]cholic and [14C]chenodeoxycholic acids. Cholic acid synthesis in cirrhotic patients was markedly depressed (170 vs. 927 mumoles per day)( while chenodeoxycholic acid synthesis was reduced to a much lesser degree (227 vs. 550 mumoles per day). The administration of [3H]7 alpha-hydroxycholesterol allowed for an evaluation of the major pathway of bile acid synthesis via the 7 alpha-hydroxylation of cholesterol. This compound was efficiently incorporated into primary bile acids by the two normal subjects (88 and 100%) and two cirrhotic patients (77 and 91%). However, the recovery of the label in cholic acid was slightly less in cirrhotic patients than in normal subjects. [3H]26-hydroxycholesterol was administered to ascertain the contribution of the 26-hydroxylation pathway to bile acid synthesis. All study subjects showed poor conversion (9 to 22%) of this intermediate into bile acids. The results of this study suggest that a major block in the bile acid synthesis pathway in cirrhosis is at the level of 7 alpha-hydroxylation of cholesterol (impairment of 7 alpha-hydroxylase) and /or in the feedback triggering mechanism regulating bile acid synthesis. The data also suggest that the 26-hydroxylation pathway in normal subjects and patients with cirrhosis is a minor contributor to synthesis of the primary bile acids. Therefore, the relative sparing of chenodeoxycholic acid synthesis observed in cirrhotic patients is not due to preferential synthesis of this bile acid via the 26-hydroxylation pathway.
为了更确切地评估晚期肝硬化患者胆酸和鹅脱氧胆酸合成中观察到的异常，通过测定[3H]7α-羟基胆固醇和[3H]26-羟基胆固醇转化为初级胆汁酸的效率，对两条胆汁酸生物合成途径进行了研究。通过给予[14C]胆酸和[14C]鹅脱氧胆酸来测定胆汁酸动力学。肝硬化患者的胆酸合成明显降低（每天170微摩尔对927微摩尔），而鹅脱氧胆酸合成降低程度较小（每天227微摩尔对550微摩尔）。给予[3H]7α-羟基胆固醇可以评估通过胆固醇7α-羟基化的胆汁酸合成主要途径。该化合物在两名正常受试者（88%和100%）和两名肝硬化患者（77%和91%）中有效地掺入初级胆汁酸。然而，肝硬化患者胆酸中标记物的回收率略低于正常受试者。给予[3H]26-羟基胆固醇以确定26-羟基化途径对胆汁酸合成的贡献作用。所有研究对象均显示该中间体转化为胆汁酸的效率较低（9%至22%）。本研究结果表明，肝硬化中胆汁酸合成途径的主要阻滞位于胆固醇7α-羟基化水平（7α-羟化酶受损）和/或调节胆汁酸合成的反馈触发机制。数据还表明，正常受试者和肝硬化患者中的26-羟基化途径对初级胆汁酸合成的贡献较小。因此，肝硬化患者中观察到的鹅脱氧胆酸合成相对保留并非由于通过26-羟基化途径优先合成该胆汁酸。
