Cytochrome P450-mediated oxidation of glucuronide derivatives:: Example of estradiol-17β-glucuronide oxidation to 2-hydroxyestradiol-17β-glucuronide by CYP2C8
Cytochrome P450-mediated oxidation of glucuronide derivatives:: Example of estradiol-17β-glucuronide oxidation to 2-hydroxyestradiol-17β-glucuronide by CYP2C8
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DOI：
10.1124/dmd.104.002097
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发表时间：
2005-03-01
影响因子：
3.9
通讯作者：
André, F
中科院分区：
文献类型：
--
作者：
Delaforge, M;Pruvost, A;André, F
在经典的代谢氧化方案中，疏水性的内源或外源化合物经历I相氧化，通常在肝脏中由细胞色素P450催化，然后是II相结合反应，以允许更多的极性代谢物通过主动运输机制从细胞中排出。已经描述了细胞色素P450介导的类固醇硫酸盐的氧化，这表明可以发生内源化合物的葡萄糖醛酸衍生物等极性代谢物的氧化。作为一个例子，我们在这里报道了羟基雌二醇-17β-葡萄糖醛酸脂可以通过将雌二醇-17β-葡萄糖醛酸氧化到芳香族C2位而直接生成。这一反应是由CYP 2C8特异性催化的，它在女性体内比男性在人类肝微粒体中更活跃。CYP2C8晶体结构中分子的完全对接表明，活性中心足够大，可以处理葡萄糖醛酸化物共轭化合物。此外，结合配体的最具能量优势的位置与最近发表的CyP2C8活性部位底物专一性的结构决定因素完全一致。这是首次证明细胞色素P450介导的类固醇葡萄糖偶联物的氧化。这种葡萄糖醛酸化物的氧化应该是一个一般的过程，因为除了雌二醇和睾酮葡萄糖醛酸化物外，还观察到了异类化合物，例如双氯芬酸或萘普生葡萄糖醛酸化物。
In the classical metabolic oxidation scheme, hydrophobic endogenous or xenobiotic compounds undergo phase I oxidation, generally catalyzed in the liver by cytochromes P450, followed by phase II conjugation reactions, in a way that allows much more polar metabolites to be expelled from the cell through active transport mechanisms. Cytochrome P450-mediated oxidation of steroid sulfate has been described, suggesting that oxidation of polar metabolites such as glucuronide derivatives of endogenous compounds can occur. As an example, we report here that hydroxyestradiol-17beta-glucuronide can be directly formed through oxidation of estradiol-17beta-glucuronide on the aromatic C2 position. This reaction is specifically catalyzed by CYP 2C8, which is more active in female than in male human liver microsomes. A thorough docking of the molecule within the CYP 2C8 crystal structure shows that the active site is large enough to handle a glucuronide conjugate. Moreover, the most energetically favored position of the bound ligand is fully consistent with the recently published structural determinants of substrate specificity of the CYP 2C8 active site. This is the first demonstration of cytochrome P450-mediated oxidation of a steroid glucuro-conjugate. Such oxidation of a glucuronide should be a general process since, in addition to estradiol and testosterone glucuronide, it has been observed for xenobiotic compounds, e. g., diclofenac or naproxen glucuronide.