塞来昔布的氧化多态细胞色素P450 2 c9和酒精脱氢酶。
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桑德伯格M Yasar U, Stromberg P,这位乔Eliasson E
塞来昔布的氧化多态细胞色素P450 2 c9和酒精脱氢酶。
Br中国新药杂志。2002年10月,54 (4):423 - 9。
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12392591 (在PubMed]
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目的:塞来昔布是一种新型选择性cyclooxygenase-2抑制剂,这是受到广泛的肝代谢。目前的体外调查的目的是1)比较塞来昔布的速度由不同的基因变异的细胞色素P450 2 c9羟基化(CYP2C9),和2)来识别所涉及的酶(s)的主要代谢物carboxycelecoxib的形成。方法:Hydroxycelecoxib形成研究在人类肝微粒体从35组肝脏、酵母以及与重组表达不同的微粒体P450变体。Carboxycelecoxib形成研究肝微粒体没有孵化或肝细胞溶质的存在。的代谢物被h.p.l.c识别和量化。此外,hydroxycelecoxib氧化的不同变体重组人类酒精脱氢酶(ADH1-3)分析了光谱光度测量的监测从NAD + NADH的一代。结果:塞来昔布的内在间隙羟基化显著降低了yeast-expressed CYP2C9.3最低为1(0.14毫升nmol-1酶)与CYP2C9.1最低为1(0.44毫升nmol-1酶)。在人类肝微粒体,显著降低2倍的速度hydroxycelecoxib形成明显在CYP2C9 * 1 / * 3样本与CYP2C9 * 1 / * 1样本。也有明显减少(5.3倍)hydroxycelecoxib形成肝脏样本这些CYP2C9 * 3 / * 3。然而,CYP2C9 * 2样品没有明显的区别于CYP2C9 * 1的系统研究。抑制实验sulphaphenazole (SPZ)内或triacetyloleandomycin表示,塞来昔布在人类肝微粒体羟基化主要是依赖于CYP2C9和CYP3A4。 The further oxidation of hydroxycelecoxib to carboxycelecoxib was completely dependent on liver cytosol and NAD+. Additional experiments showed that ADH1 and ADH2 catalysed this reaction in vitro with apparent K m values of 42 micro m and 10 micro m, respectively, whereas ADH3 showed no activity. CONCLUSIONS: The results confirm that CYP2C9 is the major enzyme for celecoxib hydroxylation in vitro and further indicate that the CYP2C9*3 allelic variant is associated with markedly slower metabolism. Furthermore, it was shown for the first time that carboxycelecoxib formation is dependent on cytosolic alcohol dehydrogenase, presumably ADH1 and/or ADH2.
