Skrede S, Björkhem I, Buchmann M S, Hopen G, Fausa O
J Clin Invest. 1985 Feb;75(2):448-55. doi: 10.1172/JCI111719.
A mixture of 7 alpha-3H- and 4-14C-labeled cholesterol was administered intravenously to rats. Cholestanol with 20-30% lower ratio between 3H and 14C than in cholesterol could be isolated from different organs. In a healthy human control, cholestanol isolated from feces had a 3H/14C ratio which was 28% lower than in administered cholesterol. Cholesterol and coprostanol reisolated in these experiments had the same ratio between 3H and 14C as in the precursor. A previously unknown pathway for formation of cholestanol, involving 7 alpha-hydroxylated intermediates, may explain these results. Under normal conditions, this pathway is responsible for at most 30% of the cholestanol synthesized from cholesterol. Intravenous administration of the 7 alpha-3H- and 4-14C-labeled cholesterol to a patient with cerebrotendinous xanthomatosis (CTX) resulted in formation of cholestanol which had 70-75% lower 3H/14C ratio. It is concluded that the novel pathway involving 7 alpha-hydroxylated intermediates is accelerated in patients with CTX. This acceleration may contribute essentially to the accumulation of cholestanol, which is a predominant feature of this disease. 7 alpha-Hydroxycholesterol and 7 alpha-hydroxy-4-cholesten-3-one might be intermediates in the novel pathway to cholestanol. After intravenous administration of 7 beta-3H-labeled 7 alpha-hydroxycholesterol in a patient with CTX, significant amounts of 3H were incorporated into plasma and fecal cholestanol. Only small amounts of 7 alpha-hydroxycholesterol and 7 alpha-hydroxy-4-cholesten-3-one are excreted into the intestine, and we therefore conclude that the 7 alpha-dehydroxylation step mainly occurs in the liver. In CTX, the synthesis of cholestanol may be accelerated because the concentrations of 7 alpha-hydroxylated bile acid intermediates in the liver are increased. A possible mechanism for the conversion of a minor fraction of 7 alpha-hydroxycholesterol into cholestanol is suggested.
将含有7α - 3H标记和4 - 14C标记的胆固醇混合物静脉注射给大鼠。从不同器官中可分离出胆甾烷醇，其3H与14C的比例比胆固醇中的低20 - 30%。在健康人体对照中，从粪便中分离出的胆甾烷醇的3H/14C比例比注射的胆固醇低28%。在这些实验中重新分离出的胆固醇和粪甾烷醇的3H与14C比例与前体中的相同。一条涉及7α - 羟基化中间体的、此前未知的胆甾烷醇形成途径可能解释了这些结果。在正常情况下，该途径最多负责由胆固醇合成的胆甾烷醇的30%。将含有7α - 3H标记和4 - 14C标记的胆固醇静脉注射给一名脑腱性黄瘤病（CTX）患者，结果形成的胆甾烷醇的3H/14C比例低70 - 75%。得出的结论是，涉及7α - 羟基化中间体的新途径在CTX患者中加速。这种加速可能在很大程度上导致了胆甾烷醇的积累，这是该疾病的一个主要特征。7α - 羟基胆固醇和7α - 羟基 - 4 - 胆甾烯 - 3 - 酮可能是胆甾烷醇新途径中的中间体。在一名CTX患者静脉注射7β - 3H标记的7α - 羟基胆固醇后，大量的3H被掺入血浆和粪便中的胆甾烷醇中。只有少量的7α - 羟基胆固醇和7α - 羟基 - 4 - 胆甾烯 - 3 - 酮排泄到肠道中，因此我们得出结论，7α - 脱羟基步骤主要发生在肝脏中。在CTX中，胆甾烷醇的合成可能会加速，因为肝脏中7α - 羟基化胆汁酸中间体的浓度增加。提出了一种将一小部分7α - 羟基胆固醇转化为胆甾烷醇的可能机制。
