Hill C E, Olson M S
Department of Biochemistry, University of Texas Health Science Center, San Antonio 78284-7760.
Biochem J. 1987 Oct 1;247(1):207-14. doi: 10.1042/bj2470207.
The stimulation of hepatic glycogenolysis by platelet activating factor (AGEPC) or increased perfusate potassium concentration ([K+]o), but not phenylephrine, causes a transient increase in uric acid release into the effluent perfusate of perfused rat livers. Uric acid was identified in chromatograms of perfusate samples using reversed-phase h.p.l.c., which show a peak which co-elutes with authentic uric acid, and by the fact that the A293 of perfusate samples decreases in the presence of uricase. Uric acid release is dose-dependent with respect to both AGEPC and [K+]o, and is blocked completely by prior exposure of the perfused liver to 5 mM-allopurinol, a specific inhibitor of xanthine oxidase (XOD). Allopurinol inhibits the increase in portal vein pressure induced by AGEPC, increased [K+]o or phenylephrine; the inhibitory effect increases with increasing concentrations of the agents. Also, allopurinol inhibits the second phase of O2 uptake and glucose release characteristic of concentrations of AGEPC or increased [K+]o equal to or greater than their reported half-maximal concentration for glucose release. The ratio of xanthine dehydrogenase (XDH) to XOD activity in extracts of freeze-clamped perfused livers is not affected by treatment of the livers with AGEPC or increased [K+]o. The results suggest that uric acid production may be an indicator of ischaemia within localized hepatic sinusoids, and that allopurinol partially protects the hepatocyte from the effects of AGEPC or increased [K+]o by inhibiting XOD-dependent superoxide production. We propose that the second phase of the glycogenolytic response to these agents results from ischaemia and subsequent reperfusion. Activation of XOD in vivo and hence O2-derived free radical production may be involved in the response of the liver to vasoactive agonists under a variety of pathophysiological conditions.
血小板激活因子（AGEPC）或灌注液钾离子浓度（[K + ]o）升高可刺激肝糖原分解，去氧肾上腺素则不能，这会使尿酸释放到灌注大鼠肝脏的流出灌注液中出现短暂增加。使用反相高效液相色谱法在灌注液样品的色谱图中鉴定出尿酸，该色谱图显示出一个与纯尿酸共洗脱的峰，并且灌注液样品在尿酸酶存在下A293降低。尿酸释放对AGEPC和[K + ]o均呈剂量依赖性，并且通过预先将灌注肝脏暴露于5 mM别嘌呤醇（一种黄嘌呤氧化酶（XOD）的特异性抑制剂）可完全阻断。别嘌呤醇可抑制AGEPC、[K + ]o升高或去氧肾上腺素诱导的门静脉压力升高；抑制作用随药物浓度增加而增强。此外，别嘌呤醇可抑制AGEPC浓度或[K + ]o升高至等于或大于其报道的葡萄糖释放半数最大浓度时所特有的氧摄取和葡萄糖释放的第二阶段。冷冻钳夹灌注肝脏提取物中黄嘌呤脱氢酶（XDH）与XOD活性的比值不受AGEPC处理或[K + ]o升高的影响。结果表明，尿酸生成可能是局部肝窦缺血的一个指标，并且别嘌呤醇通过抑制XOD依赖性超氧化物生成，部分保护肝细胞免受AGEPC或[K + ]o升高的影响。我们提出，对这些药物糖原分解反应的第二阶段是由缺血和随后的再灌注引起的。体内XOD的激活以及由此产生的氧衍生自由基可能参与了在各种病理生理条件下肝脏对血管活性激动剂的反应。
