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CYTOCHROME P450-MEDIATED OXIDATION OF GLUCURONIDE DERIVATIVES: EXAMPLE OF ESTRADIOL-17ß-GLUCURONIDE OXIDATION TO 2-HYDROXY-ESTRADIOL-17ß-GLUCURONIDE BY CYP 2C8

Service de Pharmacologie et d'Immunologie, Direction des Sciences du Vivant/Département de Recherche Médicale (M.D., A.P.); and Centre National de la Recherche Scientifique, Unité de Recherche Associée 2096, Département de Biologie Joliot Curie (M.D., L.P., F.A.), Commissariat à l'Energie Atomique, Saclay, France

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-17ß-glucuronide can be directly formed through oxidation of estradiol-17ß-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.

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