![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication August 31, 2004.
Revised December 6, 2004.
Accepted for publication December 16, 2004.
-glucuronide oxidation to 2-hydroxy-estradiol-17-glucuronide by P450-2C8
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, the way that allows such more polar metabolites to be expelled out 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 hydroxy-estradiol-17
-glucuronide can be directly formed through oxidation of estradiol-17-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 structural determinants of substrate specificity of CYP 2C8 active site recently published by Melet et al., 2004. 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 also been observed for xenobiotic compounds, e.g. diclofenac or naproxen glucuronide.
Key words:
CYP2C, cytochrome P450 catalyzed oxidations, human CYP enzymes, microsomes
This article has been cited by other articles:
|
|
 |
|
  G. A. Schoch, J. K. Yano, S. Sansen, P. M. Dansette, C. D. Stout, and E. F. Johnson Determinants of Cytochrome P450 2C8 Substrate Binding: STRUCTURES OF COMPLEXES WITH MONTELUKAST, TROGLITAZONE, FELODIPINE, AND 9-CIS-RETINOIC ACID J. Biol. Chem., June 20, 2008; 283(25): 17227 - 17237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Albrecht, A. Unger, A. K. Nussler, and S. Laufer In Vitro Metabolism of 2-[6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] Acetic Acid (Licofelone, ML3000), an Inhibitor of Cyclooxygenase-1 and -2 and 5-Lipoxygenase Drug Metab. Dispos., May 1, 2008; 36(5): 894 - 903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wang, D. Zhang, A. Swaminathan, Y. Xue, P. T. Cheng, S. Wu, R. Mosqueda-Garcia, C. Aurang, D. W. Everett, and W. G. Humphreys GLUCURONIDATION AS A MAJOR METABOLIC CLEARANCE PATHWAY OF 14C-LABELED MURAGLITAZAR IN HUMANS: METABOLIC PROFILES IN SUBJECTS WITH OR WITHOUT BILE COLLECTION Drug Metab. Dispos., March 1, 2006; 34(3): 427 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. W. Ogilvie, D. Zhang, W. Li, A. D. Rodrigues, A. E. Gipson, J. Holsapple, P. Toren, and A. Parkinson GLUCURONIDATION CONVERTS GEMFIBROZIL TO A POTENT, METABOLISM-DEPENDENT INHIBITOR OF CYP2C8: IMPLICATIONS FOR DRUG-DRUG INTERACTIONS Drug Metab. Dispos., January 1, 2006; 34(1): 191 - 197. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
