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: The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel.
    Author: Gentile DM, Verhoeven CH, Shimada T, Back DJ.
    Journal: J Pharmacol Exp Ther; 1998 Dec; 287(3):975-82. PubMed ID: 9864282.
    Abstract:
    Desogestrel is a 3-deoxo progestogenic steroid that requires bioactivation to 3-ketodesogestrel. In these studies we have attempted to define the pathway of 3-ketodesogestrel formation and characterise the enzymes responsible for this biotransformation in vitro. Initial studies using deuterated desogestrel confirmed that desogestrel is metabolised by human liver microsomes via 3alpha-hydroxy and 3beta-hydroxydesogestrel to 3-ketodesogestrel. Metabolites were analysed by radiometric high-performance liquid chromatography and were identified by liquid chromatography-mass spectrometry and by cochromatography with authentic standards. Desogestrel was metabolised by microsomes from lymphoblasts containing cDNA-expressed CYP2C9 and CYP2C19 to 3alpha-hydroxydesogestrel with small amounts of 3beta-hydroxydesogestrel also being observed. The Km value for 3alpha-hydroxylation by CYP2C9 cell line microsomes was 6.5 microM and the corresponding Vmax value was 1269 pmole. mg-1. min-1. Sulfaphenazole potently inhibited 3alpha-hydroxydesogestrel formation by CYP2C9 microsomes with a Ki value of 0.91 microM. There was a significant negative correlation between 3-ketodesogestrel and CYP3A4 content/activity in a panel of human livers suggesting that the further metabolism of 3-ketodesogestrel is mediated by CYP3A4. Sulfaphenazole partially inhibited 3alpha-hydroxydesogestrel and 3-ketodesogestrel formation in human liver microsomes indicating a possible in vivo role for CYP2C9. In addition, when sulfaphenazole was combined with S-mephenytoin, further inhibition of 3alpha-hydroxydesogestrel formation was observed suggesting a possible role for CYP2C19. This was confirmed in incubations with inhibitory antibodies. Whereas an anti-CYP2C9/2C19 antibody completely abolished desogestrel metabolism, anti-CYP3A4 and anti-CYP2E1 were not inhibitory. We conclude that CYP2C9 and possibly CYP2C19 and important isoforms catalysing the initial hydroxylation of desogestrel. Desogestrel is a 3-deoxy progestogenic oral contraceptive steroid which requires bioactivation to 3-ketodesogestrel. Initial studies using deuterated desogestrel have confirmed that desogestrel is metabolized by human liver microsomes through 3(alpha)-hydroxy and 3(beta)-hydroxydesogestrel to 3-ketodesogestrel. While the enzymes responsible for the bioactivation of desogestrel have never been formally identified, there is some evidence for the involvement of CYP isoforms. The CYP family of enzymes is responsible for the oxidation of structurally diverse lipophilic chemicals and plays an important role in the hydroxylation of endogenous steroids leading to the biosynthesis of all major classes of steroid hormones. The authors investigated the pathway of 3-ketodesogestrel formation and characterize the enzymes responsible for that biotransformation in vitro. Their research materials and methodology is described in detail. They conclude that CYP2C9 and possibly CYP2C19 are important isoforms which catalyze the initial hydroxylation of desogestrel.
    [Abstract] [Full Text] [Related] [New Search]