Prostaglandin synthetase catalyzed activation of paracetamol.
Prostaglandin synthetase catalyzed activation of paracetamol.
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前列腺素合成酶催化对乙酰氨基酚的活化。
DOI：
10.1016/0006-2952(82)90029-6
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发表时间：
1982
影响因子：
5.8
通讯作者：
Margareta Berggren
中科院分区：
文献类型：
--
作者：
P. Moldéus;Bo Andersson;Anver D. Rahimtula;Margareta Berggren
前列腺素合成酶能够催化对乙酰氨基酚代谢为反应性代谢产物，该代谢产物与蛋白质和还原型谷胱甘肽（GSH）结合。从绵羊精囊（SSV）和兔肾髓质分离的微粒体证明了这一点。在前列腺素生物合成过程中，对乙酰氨基酚的活化通过共氧化发生，该酶的过氧化物酶活性负责该反应。除了被代谢，扑热息痛也刺激前列腺素生物合成的速率，可能是作为一种有效的氢供体。对乙酰氨基酚代谢为反应性代谢物最可能涉及对乙酰氨基酚自由基物质的形成。抗氧化剂丁基羟基茴香醚的抑制作用以及前列腺素合成酶催化反应过程中GSH的快速氧化表明了这一点。这种对乙酰氨基酚自由基是否在与GSH或蛋白质反应之前被进一步氧化为醌亚胺，仍有待确定。由于谷胱甘肽结合物明显相同，因此最终反应性代谢产物显然与肝微粒体和NADPH形成的代谢产物相同。然而，SSV微粒体对扑热息痛的活化速率是肝微粒体的100倍以上，而且表观Km值相当低。最后，在花生四烯酸存在的情况下，前列腺素合成酶可将N-OH对乙酰氨基酚活化为明显不同于对乙酰氨基酚的代谢产物。
Prostaglandin synthetase has the ability to catalyze the metabolism of paracetamol to a reactive metabolite, which binds to protein and reduced glutathione (GSH). This was demonstrated with microsomes isolated from both sheep seminal vesicles (SSV) and rabbit kidney medulla. The activation of paracetamol occurred through cooxygenation during prostaglandin biosynthesis, the peroxidase activity of this enzyme being responsible for the reaction. In addition to being metabolized, paracetamol also stimulated the rate of prostaglandin biosynthesis, probably by serving as a potent hydrogen donor. The metabolism of paracetamol to a reactive metabolite most likely involved the formation of a paracetamol radical species. This was indicated by an inhibitory effect of the antioxidant, butylated hydroxyanisole, as well as by a very rapid oxidation of GSH during the course of the prostaglandin synthetase catalyzed reaction. Whether this paracetamol radical is further oxidized to the quinone imine prior to reacting with GSH or protein, remains to be established. The ultimate reactive metabolite is evidently the same as that formed with liver microsomes and NADPH since the glutathione conjugates were apparently identical. The rate of paracetamol activation by SSV microsomes was, however, more than 100 times that by liver microsomes and furthermore the apparentKmwas considerably lower. Finally,N-OH paracetamol was shown to be activated by prostaglandin synthetase in the presence of arachidonic acid to a metabolite apparently different from that formed from paracetamol.
影响因子：
2.9
作者：
REED, DJ;BABSON, JR;POTTER, DW
通讯作者：
POTTER, DW