Gylling H, Vanhanen H, Miettinen T A
Second Department of Medicine, University of Helsinki, Finland.
J Lipid Res. 1993 Jan;34(1):59-67.
Ketoconazole, an inhibitor of cholesterol synthesis at 14 alpha-demethylation of lanosterol, effectively reduces serum total and low density lipoprotein (LDL) cholesterol levels. We studied the effects of ketoconazole (400 mg/day for 5 weeks) on serum lipids, free and esterified noncholesterol sterols, and kinetics of LDL apolipoprotein B (apoB) in seven patients with heterozygous familial hypercholesterolemia (FH) and in three patients with primary hypercholesterolemia (nonFH). The total, intermediate density, and LDL cholesterol levels were significantly reduced by 24, 27, and 29%, respectively, and LDL apoB by 23%. Serum total and lipoprotein triglycerides were unchanged. The LDL cholesterol/apoB ratio decreased significantly. Serum ratios of lanosterols to cholesterol were increased over 50 times, almost the same in all lipoproteins and mainly as the unesterified form; free delta 8-precursor sterols, 2-5 times; cholestanol, slightly; while ratios of lanosterol of desmosterol, lathosterol, and plant sterols were virtually unchanged. Inconsistent esterification of methyl sterols might indicate unaltered acyl CoA:cholesterol acyltransferase activity. LDL apoB transport was decreased in all nonFH subjects but inconsistently in FH. The fractional catabolism rate (FCR) for LDL apoB was increased significantly in FH by 13% and inconsistently by 4% in nonFH. In a subgroup of three FH patients, more dense LDL (d 1.037-1.055 g/ml) was transported and catabolized faster on than off ketoconazole so that the serum level of this more dense LDL subfraction was unchanged, the decrease of LDL being due to a reduction of the less dense LDL subfraction.(ABSTRACT TRUNCATED AT 250 WORDS)
酮康唑是羊毛甾醇14α-去甲基化过程中胆固醇合成的抑制剂，能有效降低血清总胆固醇和低密度脂蛋白（LDL）胆固醇水平。我们研究了酮康唑（400毫克/天，持续5周）对7例杂合子家族性高胆固醇血症（FH）患者和3例原发性高胆固醇血症患者（非FH）的血脂、游离及酯化非胆固醇甾醇以及LDL载脂蛋白B（apoB）动力学的影响。总胆固醇、中间密度脂蛋白和LDL胆固醇水平分别显著降低了24%、27%和29%，LDL apoB降低了23%。血清总甘油三酯和脂蛋白甘油三酯未发生变化。LDL胆固醇/apoB比值显著降低。羊毛甾醇与胆固醇的血清比值增加了50多倍，在所有脂蛋白中几乎相同，且主要以未酯化形式存在；游离δ8-前体甾醇增加了2 - 5倍；胆甾烷醇略有增加；而羊毛甾醇与麦角甾醇、羊毛甾醇与植物甾醇的比值基本未变。甲基甾醇酯化不一致可能表明酰基辅酶A：胆固醇酰基转移酶活性未改变。所有非FH受试者的LDL apoB转运均降低，但FH患者的情况不一致。FH患者中LDL apoB的分数分解代谢率（FCR）显著增加了13%，非FH患者则不一致地增加了4%。在一个由3例FH患者组成的亚组中，酮康唑治疗期间比未治疗时，密度更高的LDL（d 1.037 - 1.055克/毫升）转运和分解代谢更快，因此该密度更高的LDL亚组分的血清水平未变，LDL的降低是由于密度较低的LDL亚组分减少所致。（摘要截取自250字）
