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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Dexamethasone metabolism by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation.

The metabolism of the synthetic glucocorticoid dexamethasone in human liver microsomal incubations has been studied. Metabolites were analyzed by radiometric high-performance liquid chromatography and were identified by liquid-chromatography-mass spectrometry; in addition, the major metabolite 6beta-hydroxydexamethasone was identified by cochromatography with a chemically synthesized standard. A total of 17 human livers were used in this study and the following metabolites were identified: 6beta-hydroxydexamethasone, 6 alpha-hydroxydexamethasone, 6-hydroxy-9 alpha-fluoro-androsta-1,4-diene-11 beta-hydroxy-16 alpha-methyl-3,17-dione (6-hydroxy-9 alpha-F-A) and 9 alpha-fluoro-androsta-1,4-diene-11 beta-hydroxy-16 alpha-methyl-3,17-dione (9 alpha-F-A). Dexamethasone underwent side-chain cleavage to form 9 alpha-F-A. This metabolite was then a substrate for 6-hydroxylation. There was considerable interindividual variability in metabolic profiles. Mean (+/-S.D.) K(m) values for 6 beta- and 6 alpha-hydroxydexamethasone formation were 23.2 +/- 3.8 and 25.6 +/- 1.6 microM (n = 4), respectively. The corresponding V max values were 14.3 +/- 9.9 and 4.6 +/- 3.1 pmol x min(-1) mg protein (-1). Ketoconazole (3 microM) completely inhibited 6 alpha- and 6 beta-hydroxylation, indicating that formation of both metabolites was catalyzed by CYP3A4. This was confirmed in studies of correlations between the rate of metabolite formation and the relative expression of CYP3A4: r = 0.74 for 6 beta-hydroxydexamethasone, P = .003; r = 0.70 for 6 alpha-hydroxydexamethasone, P = .006. In addition to ketoconazole, both ellipticine and gestodene caused marked inhibition of 6-hydroxylation. Ellipticine is clearly not a selective CYP1A inhibitor as has been stated previously. However, furafylline (CYP1A inhibitor), tolbutamide ( CYP2C substrate), and sulfaphenazole ( CYP2C inhibitor) were essentially noninhibitory. The relatively simple metabolic profile of dexamethasone compared to other steroids may point to this being a potentially useful in vivo probe for CYP3A4 in humans.[1]


  1. Dexamethasone metabolism by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation. Gentile, D.M., Tomlinson, E.S., Maggs, J.L., Park, B.K., Back, D.J. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
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