INHIBITION OF 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE BY MEVINOLIN IN FAMILIAL HYPERCHOLESTEROLEMIA HETEROZYGOTES - EFFECTS ON CHOLESTEROL BALANCE
INHIBITION OF 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE BY MEVINOLIN IN FAMILIAL HYPERCHOLESTEROLEMIA HETEROZYGOTES - EFFECTS ON CHOLESTEROL BALANCE
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DOI：
10.1073/pnas.81.8.2538
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发表时间：
1984-01-01
期刊：
影响因子：
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通讯作者：
BILHEIMER, DW
中科院分区：
文献类型：
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作者：
GRUNDY, SM;BILHEIMER, DW
杂合子型家族性高胆固醇血症（FH）患者血浆低密度脂蛋白（LDL）受体缺乏，损害LDL从血浆中的清除。在这些患者中，3-羟基-3-甲基戊二酰-CoA还原酶[甲羟戊酸：NAD+氧化还原酶（CoA-酰化），EC 1.1.1.88]的抑制剂mevinolin可增加LDL受体并降低LDL浓度。为了确定美维诺林是否也会导致胆固醇的全身合成严重减少，在用美维诺林治疗之前和期间，在5个FH杂合子中测定了中性类固醇和酸性类固醇的粪便排泄。该药物使血浆总胆固醇平均降低23%，LDL胆固醇平均降低24%。美维诺林引起3例患者中性和酸性类固醇输出的显著减少，但在另外2例患者中未引起改变。类固醇粪便排出量的变化与患者LDL-胆固醇水平降低的程度无关。没有一个患者的粪便类固醇排出量低于在类似条件下研究的正常受试者中观察到的值。1例患者既往接受过回肠切除术，在对照期内大量排出酸性类固醇;美维诺林治疗导致酸性类固醇排泄轻微减少，但排出量仍明显高于正常。美维诺林的降LDL作用似乎不需要严重降低胆固醇合成，这可能导致胆固醇的重要体内储存耗尽。
Patients with heterozygous familial hypercholesterolemia (FH) have a deficiency of receptors for plasma low-density lipoprotein (LDL) that impairs removal of LDL from plasma. In these patients, mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase [mevalonate:NAD+ oxidoreductase (CoA-acylating), EC 1.1.1.88], increases receptors for LDL and decreases LDL concentrations. To determine whether mevinolin also causes severe decreases in total body synthesis of cholesterol, fecal excretions of neutral steroids and acidic steroids were determined in 5 FH heterozygotes before and during treatment with mevinolin. The drug produced an average decrease in plasma total cholesterol of 23% and in LDL cholesterol of 24%. Mevinolin caused a significant decrease in the output of neutral and acidic steroids in 3 patients, but it caused no alterations in 2 others. Changes in fecal output of steroids did not correlate with the degree of lowering of the patients'' LDL-cholesterol level. In none of the patients did the output of fecal steroids fall below the values seen in normal subjects studied under similar conditions. One patient had a previous ileal exclusion operation and had a massive output of acidic steroids in the control period; mevinolin therapy caused a slight decrease in excretion of acidic steroids, but the output was still markedly above normal. The LDL lowering action of mevinolin does not appear to require a severe decrease in cholesterol synthesis that might lead to depletion of vital body stores of cholesterol.