McNamara D J, Ahrens E H, Parker T S, Morrissey K
J Clin Invest. 1985 Jul;76(1):31-9. doi: 10.1172/JCI111962.
Studies were carried out in humans and in rhesus monkeys to determine the role of the kidneys in the metabolism of circulating mevalonic acid (MVA). Following intravenous infusion of [14C]MVA and [3H]cholesterol, there was a rapid appearance of [14C]squalene in the kidneys that exhibited a significantly longer half-life than plasma or hepatic squalene. In man and in rhesus monkeys there was a rapid equilibration between newly synthesized cholesterol from MVA and exogenously administered cholesterol in all tissues except the kidneys, where the specific activity ratio of newly synthesized to exogenous cholesterol was significantly higher. Estimates of the quantitative metabolism of intravenously infused radiolabeled MVA in the monkey demonstrated that 23% was excreted in the urine, 67% metabolized to cholesterol (58% in nonrenal tissues and 9% in the kidneys), and 10% catabolized to CO2 and nonsteroid products. Measurements of MVA metabolism in anephric and uninephric patients demonstrate that, in the absence of renal uptake of MVA, exogenous and newly synthesized cholesterol achieve almost instantaneous equilibrium in the plasma; whereas in control subjects with normal renal function, this equilibration required at least 21 d for the two cholesterol decay curves to become parallel. These results suggest that the kidneys are solely responsible for the observed disequilibrium between newly synthesized and exogenous cholesterol; we suggest that this was due to the delayed release of newly synthesized cholesterol from the kidneys into the plasma compartment following intravenous infusion with radiolabeled MVA. The data document the importance of the kidneys in the metabolism of circulating MVA. However, calculation of the quantitative significance of this pathway in relation to whole body MVA metabolism indicates that renal metabolism of MVA accounts for approximately 0.1% of daily MVA turnover, and that alterations in this pathway due to any form of renal pathology would not result in significant changes in hepatic or whole body sterol synthesis rates. We urge caution in the use of radiolabeled MVA in long-term kinetic studies of sterol metabolism because our data show that the plasma compartment of MVA is not necessarily in isotopic equilibrium with tissue MVA.
开展了人体和恒河猴研究，以确定肾脏在循环甲羟戊酸（MVA）代谢中的作用。静脉输注[14C]MVA和[3H]胆固醇后，肾脏中迅速出现[14C]角鲨烯，其半衰期明显长于血浆或肝脏中的角鲨烯。在人类和恒河猴中，除肾脏外，所有组织中由MVA新合成的胆固醇与外源性给予的胆固醇之间迅速达到平衡，而在肾脏中，新合成胆固醇与外源性胆固醇的比活性显著更高。对静脉输注放射性标记MVA的猴子进行定量代谢估计表明，23%经尿液排泄，67%代谢为胆固醇（58%在非肾组织，9%在肾脏），10%分解代谢为CO2和非甾体产物。对无肾和单肾患者的MVA代谢测量表明，在没有肾脏摄取MVA的情况下，外源性和新合成的胆固醇在血浆中几乎瞬间达到平衡；而在肾功能正常的对照受试者中，这种平衡需要至少21天，两条胆固醇衰变曲线才能平行。这些结果表明，肾脏是新合成胆固醇与外源性胆固醇之间观察到的不平衡的唯一原因；我们认为这是由于静脉输注放射性标记MVA后，新合成的胆固醇从肾脏释放到血浆隔室的延迟所致。这些数据证明了肾脏在循环MVA代谢中的重要性。然而，计算该途径相对于全身MVA代谢的定量意义表明，MVA的肾脏代谢约占每日MVA周转的0.1%，并且由于任何形式的肾脏病理导致该途径的改变不会导致肝脏或全身甾醇合成速率的显著变化。我们敦促在甾醇代谢的长期动力学研究中谨慎使用放射性标记的MVA，因为我们的数据表明，MVA的血浆隔室不一定与组织MVA处于同位素平衡状态。
