These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Cortisol metabolism in vitro--III. Inhibition of microsomal 6 beta-hydroxylase and cytosolic 4-ene-reductase.
    Author: Abel SM, Back DJ.
    Journal: J Steroid Biochem Mol Biol; 1993 Dec; 46(6):827-32. PubMed ID: 8274418.
    Abstract:
    The in vitro metabolism of cortisol in human liver fractions is highly complex and variable. Cytosolic metabolism proceeds predominantly via A-ring reduction (to give 3 alpha,5 beta-tetrahydrocortisol; 3 alpha,5 beta-THF), while microsomal incubations generate upto 7 metabolites, including 6 beta-hydroxycortisol (6 beta-OHF), and 6 beta-hydroxycortisone (6 beta-OHE), products of the cytochrome P450 (CYP) 3A subfamily. The aim of the present study was, therefore, to examine two of the main enzymes involved in cortisol metabolism, namely, microsomal 6 beta-hydroxylase and cytosolic 4-ene-reductase. In particular, we wished to assess the substrate specificity of these enzymes and identify compounds with inhibitory potential. Incubations for 30 min containing [3H]cortisol, potential inhibitors, microsomal or cytosolic protein (3 mg), and co-factors were followed by radiometric HPLC analysis. The Km value for 6 beta-OHF and 6 beta-OHE formation was 15.2 +/- 2.1 microM (mean +/- SD; n = 4) and the Vmax value 6.43 +/- 0.45 pmol/min/mg microsomal protein. The most potent inhibitor of cortisol 6 beta-hydroxylase was ketoconazole (Ki = 0.9 +/- 0.4 microM; n = 4), followed by gestodene (Ki = 5.6 +/- 0.6 microM) and cyclosporine (Ki = 6.8 +/- 1.4 microM). Both betamethasone and dexamethasone produced some inhibition (Ki = 31.3 and 54.5 microM, respectively). However, substrates for CYP2C (tolbutamide), CYP2D (quinidine), and CYP1A (theophylline) were essentially non-inhibitory. The Km value for cortisol 4-ene-reductase was 26.5 +/- 11.2 microM (n = 4) and the Vmax value 107.7 +/- 46.0 pmol/min/mg cytosolic protein. The most potent inhibitors were androstendione (Ki = 17.8 +/- 3.3 microM) and gestodene (Ki = 23.8 +/- 3.8 microM). Although both compounds have identical A-rings to cortisol, and undergo reduction, inhibition was non-competitive.
    [Abstract] [Full Text] [Related] [New Search]