Spector T
Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Biochem Pharmacol. 1988 Jan 15;37(2):349-52. doi: 10.1016/0006-2952(88)90739-3.
A recent study of the mechanism by which oxypurinol inhibits uric acid generation [T. Spector, W. W. Hall and T. A. Krenitsky, Biochem. Pharmac. 35, 3109(1986)] showed that xanthine is ineffective in impeding the binding of oxypurinol to reduced xanthine oxidase. This study prompted the present hypothesis that, at elevated concentrations of substrates, oxypurinol would be superior to allopurinol as an inhibitor of the xanthine oxidase-catalyzed production of superoxide radical. It was found that the potency of allopurinol was attenuated by elevated concentrations of xanthine and hypoxanthine, whereas the potency of oxypurinol was relatively unaffected. Oxypurinol produced immediate inhibition of superoxide radical production as well as progressive inhibition with time. In contrast, allopurinol, which is also a substrate for xanthine oxidase, produced very little immediate inhibition and caused progressive inhibition only after conversion to oxypurinol. The theoretical advantages of treating ischemic tissues with oxypurinol are discussed.
最近一项关于氧嘌呤醇抑制尿酸生成机制的研究[T. 斯佩克特、W. W. 霍尔和T. A. 克伦尼茨基，《生物化学与药物学》35, 3109(1986)]表明，黄嘌呤在阻止氧嘌呤醇与还原型黄嘌呤氧化酶结合方面无效。这项研究促使提出了当前的假说，即在底物浓度升高时，作为黄嘌呤氧化酶催化产生超氧阴离子的抑制剂，氧嘌呤醇将优于别嘌呤醇。研究发现，黄嘌呤和次黄嘌呤浓度升高会削弱别嘌呤醇的效力，而氧嘌呤醇的效力相对不受影响。氧嘌呤醇能立即抑制超氧阴离子的产生，并随时间逐渐抑制。相比之下，别嘌呤醇也是黄嘌呤氧化酶的底物，它几乎没有立即抑制作用，只有在转化为氧嘌呤醇后才会产生逐渐抑制作用。文中讨论了用氧嘌呤醇治疗缺血组织的理论优势。
