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首页> 美国卫生研究院文献>The Journal of Clinical Investigation >Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.
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Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

机译：新型非竞争性抑制剂对大鼠肝脏羟甲基戊二酰辅酶A还原酶的调节。二氯乙酸盐和相关羧酸对酶活性的影响。

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摘要

Dichloroacetate (DCA) markedly reduces circulating cholesterol levels in animals and in patients with combined hyperlipoproteinemia or homozygous familial hypercholesterolemia (FH). To investigate the mechanism of its cholesterol-lowering action, we studied the effects of DCA and its hepatic metabolites, glyoxylate and oxalate, on the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) obtained from livers of healthy, reverse light-cycled rats. Oral administration of DCA for 4 d decreased HMG CoA reductase activity 46% at a dose of 50 mg/kg per d, and 82% at a dose of 100 mg/kg per d. A 24% decrease in reductase activity was observed as early as 1 h after a single dose of 50 mg/kg DCA. The inhibitory effect of the drug was due to a fall in both expressed enzyme activity and the total number of reductase molecules present. DCA also decreased reductase activity when added to suspensions of isolated hepatocytes. With chronic administration, DCA inhibited 3H2O incorporation into cholesterol by 38% and into triglycerides by 52%. When liver microsomes were incubated with DCA, the pattern of inhibition of reductase activity was noncompetitive for both HMG CoA (inhibition constant [Ki] 11.8 mM) and NADPH (Ki 11.6 mM). Inhibition by glyoxylate was also noncompetitive for both HMG CoA (Ki 1.2 mM) and NADPH (Ki 2.7 mM). Oxalate inhibited enzyme activity only at nonsaturating concentrations of NADPH (Ki 5.6 mM). Monochloroacetate, glycollate, and ethylene glycol, all of which can form glyoxylate, also inhibited reductase activity. Using solubilized and 60-fold purified HMG CoA reductase, we found that the inhibitory effect of glyoxylate was reversible. Furthermore, the inhibition by glyoxylate was an effect exerted on the reductase itself, rather than on its regulatory enzymes, reductase kinase and reductase phosphatase. We conclude that the cholesterol-lowering effect of DCA is mediated, at least in part, by inhibition of endogenous cholesterol synthesis. The probable mechanisms are by inhibition of expressed reductase activity by DCA per se and by conversion of DCA to an active metabolite, glyoxylate, which noncompetitively inhibits HMG CoA reductase. These studies thus identify a new class of pharmacological agents that may prove useful in regulating cholesterol synthesis and circulating cholesterol levels in man.
机译：二氯乙酸盐（DCA）可以显着降低动物以及合并高脂蛋白血症或纯合子家族性高胆固醇血症（FH）的患者的循环胆固醇水平。为了研究其降胆固醇作用的机制，我们研究了DCA及其肝代谢产物乙醛酸和草酸对健康肝脏中3-羟基-3-甲基戊二酰辅酶A还原酶（HMG CoA还原酶）活性的影响。 ，反转轻循环大鼠。口服DCA 4天后，HMG CoA还原酶活性以50 mg / kg / d的剂量降低了46％，而以100 mg / kg / d的剂量降低了82％。早在单剂量50 mg / kg DCA后1小时，观察到还原酶活性降低了24％。该药物的抑制作用是由于表达的酶活性和存在的还原酶分子总数下降。当添加到分离的肝细胞悬液中时，DCA还降低了还原酶活性。通过长期给药，DCA抑制3H2O掺入胆固醇的比例达到38％，而抑制甘油三酸酯的比例达到52％。当肝微粒体与DCA一起孵育时，还原酶活性的抑制模式对于HMG CoA（抑制常数[Ki] 11.8 mM）和NADPH（Ki 11.6 mM）都是不竞争的。乙醛酸的抑制对于HMG CoA（Ki 1.2 mM）和NADPH（Ki 2.7 mM）也是不竞争的。草酸盐仅在非饱和浓度的NADPH（Ki 5.6 mM）时抑制酶活性。一氯乙酸酯，乙醇酸酯和乙二醇均可形成乙醛酸酯，它们也抑制了还原酶的活性。使用溶解的和60倍纯化的HMG CoA还原酶，我们发现乙醛酸的抑制作用是可逆的。此外，乙醛酸的抑制作用是对还原酶本身的作用，而不是对其调节酶，还原酶激酶和还原酶磷酸酶的作用。我们得出结论，DCA的降胆固醇作用至少部分是通过抑制内源性胆固醇的合成来介导的。可能的机制是通过DCA本身抑制表达的还原酶活性，以及​​将DCA转化为活性代谢产物乙醛酸酯，后者非竞争性地抑制HMG CoA还原酶。因此，这些研究确定了一类新的药理剂，可证明对调节人体内胆固醇合成和循环胆固醇水平有用。

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