Sacerdoti D, Balazy M, Angeli P, Gatta A, McGiff J C
Department of Clinical Medicine, Splenoepatologia, University of Padova, Italy.
J Clin Invest. 1997 Sep 1;100(5):1264-70. doi: 10.1172/JCI119640.
The cytochrome P450 system transforms AA to hydroxyeicosatetraenoic acid (HETE) metabolites that are vasoactive and affect transport in several nephron segments. A principal product of this system, 20-HETE, participates in key mechanisms that regulate the renal circulation and extracellular fluid volume. We hypothesized that excess production of 20-HETE, which constricts the renal vasculature, contributes to the renal functional disturbances in patients with hepatic cirrhosis, particularly the depression of renal hemodynamics. The development of a precise and sensitive gas chromatographic/mass spectrometric method makes it possible to measure 20-HETE and the subterminal HETEs (16-,17-,18-, and 19-HETEs) in biological fluids. As 20-HETE was excreted as the glucuronide conjugate, measurement of 20-HETE required treatment of urine with glucuronidase. We measured HETEs in the urine of patients with cirrhosis, and compared these values to those of normal subjects. Urinary excretion rate of 20-HETE was highest in patients with ascites; 12.5+/-3.2 ng/min vs. 5.0+/-1.5 and 1.6+/-0.2 ng/min in cirrhotic patients without ascites and in normal subjects, respectively. Excretion of 16-, 17-, and 18-HETEs was not increased. In patients with cirrhosis, the excretory rate of 20-HETE was several-fold higher than those of prostaglandins and thromboxane, whereas in normal subjects 20-HETE and prostaglandins were excreted at similar rates. Of the eicosanoids, only increased excretion of 20-HETE in subjects with cirrhosis was correlated (r = -0.61; P < 0.01) with reduction of renal plasma flow (RPF).
细胞色素P450系统将花生四烯酸转化为具有血管活性的羟基二十碳四烯酸（HETE）代谢产物，并影响多个肾单位节段的转运。该系统的主要产物20-HETE参与调节肾循环和细胞外液量的关键机制。我们推测，导致肾血管收缩的20-HETE过量产生，会导致肝硬化患者出现肾功能障碍，尤其是肾血流动力学降低。一种精确灵敏的气相色谱/质谱法的开发，使得测量生物体液中的20-HETE和末端亚基HETE（16-、17-、18-和19-HETE）成为可能。由于20-HETE以葡萄糖醛酸共轭物的形式排泄，因此测量20-HETE需要用葡萄糖醛酸酶处理尿液。我们测量了肝硬化患者尿液中的HETE，并将这些值与正常受试者的值进行比较。腹水患者的20-HETE尿排泄率最高；分别为12.5±3.2 ng/min，而无腹水的肝硬化患者和正常受试者分别为5.0±1.5 ng/min和1.6±0.2 ng/min。16-、17-和18-HETE的排泄没有增加。在肝硬化患者中，20-HETE的排泄率比前列腺素和血栓素高几倍，而在正常受试者中，20-HETE和前列腺素的排泄率相似。在类花生酸中，只有肝硬化患者20-HETE排泄增加与肾血浆流量（RPF）降低相关（r = -0.61；P < 0.01）。
