Balasubramaniam S, Goldstein J L, Faust J R, Brown M S
Proc Natl Acad Sci U S A. 1976 Aug;73(8):2564-8. doi: 10.1073/pnas.73.8.2564.
The adenine analogue 4-aminopyrazolopyrimidine has been reported previously to reduce the hepatic secretion of plasma lipoproteins in rats, thereby lowering the plasma cholesterol level. In the current studies, reduction of the plasma cholesterol level by 90% in rats through the administration of aminopyrazolopyrimidine was found to be associated with a 5- to 30-fold increase in the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate:NADP+ oxidoreductase (CoA-acylating), EC1.1.1.34] in kidney and lung. In both tissues, the enhanced activity of this microsomal enzyme was associated with a 3-fold elevation in the rate of cholesterol synthesis from either [14C]acetate or [14C]octanoate. Comparable increases were not observed in the activities of several other microsomal enzymes or in the rates of [14C]acetate incorporation into saponifiable lipids or CO2. When administration of 4-aminopyrazolopyrimidine was terminated, plasma cholesterol levels rose and 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity declined in the kidney in a reciprocal manner. These data are consistent with the hypothesis that the low levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and cholesterol synthesis that are normally observed in certain nonhepatic tissues of the rat are due to an active form of feedback regulation mediated by cholesterol carried in plasma lipoproteins.
据先前报道，腺嘌呤类似物4-氨基吡唑并嘧啶可降低大鼠血浆脂蛋白的肝脏分泌，从而降低血浆胆固醇水平。在当前的研究中，发现通过给予氨基吡唑并嘧啶使大鼠血浆胆固醇水平降低90%与肾和肺中3-羟基-3-甲基戊二酰辅酶A还原酶[mevalonate:NADP+氧化还原酶(辅酶A酰化)，EC1.1.1.34]活性增加5至30倍有关。在这两种组织中，这种微粒体酶活性的增强与[14C]乙酸盐或[14C]辛酸酯的胆固醇合成速率提高3倍有关。在其他几种微粒体酶的活性或[14C]乙酸盐掺入可皂化脂质或二氧化碳的速率方面未观察到类似的增加。当终止4-氨基吡唑并嘧啶的给药时，血浆胆固醇水平升高，肾中3-羟基-3-甲基戊二酰辅酶A还原酶活性以相反的方式下降。这些数据与以下假设一致，即正常情况下在大鼠某些非肝脏组织中观察到的低水平3-羟基-3-甲基戊二酰辅酶A还原酶活性和胆固醇合成是由于血浆脂蛋白携带的胆固醇介导的一种活性形式的反馈调节所致。
