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Research ArticleArticle

The Role of CYP2C in the In Vitro Bioactivation of the Contraceptive Steroid Desogestrel

Daniela M. Gentile, Carole H. J. Verhoeven, Tsutomu Shimada and David J. Back
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 975-982;
Daniela M. Gentile
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Carole H. J. Verhoeven
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Tsutomu Shimada
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David J. Back
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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 3α-hydroxy and 3β-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 3α-hydroxydesogestrel with small amounts of 3β-hydroxydesogestrel also being observed. TheKm value for 3α-hydroxylation by CYP2C9 cell line microsomes was 6.5 μM and the corresponding Vmaxvalue was 1269 pmole · mg−1 · min−1. Sulfaphenazole potently inhibited 3α-hydroxydesogestrel formation by CYP2C9 microsomes with aKi value of 0.91 μM. 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 3α-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 3α-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.

Footnotes

  • Send reprint requests to: Dr. David J. Back, Department of Pharmacology and Therapeutics, New Medical Building, Ashton Street, Liverpool, L69 3GE, United Kingdom.

  • ↵1 Current address: Department of Toxicology and Drug Disposition, N.V. Organon, PO Box 20, 5340 BH OSS, The Netherlands.

  • ↵2 Current address: Osaka Prefectural Institute of Public Health, Nakamichi, Higashinari-Ku, Osaka 537, Japan.

  • Abbreviations:
    DSG
    desogestrel
    3-KDSG
    3-ketodesogestrel
    3α-OHDSG
    3α-hydroxydesogestrel
    3β-OHDSG
    3β-hydroxydesogestrel
    CYP
    cytochrome P450
    EE2
    ethinylestradial
    HPLC
    high-performance liquid chromatography
    G6P
    glucose 6-phosphate
    NADP
    nicotinamide adenine dinucleotide phosphate
    NADPH
    β-reduced form
    TOL
    tolbutamide
    SULF
    sulfaphenazole
    S-MEPH
    S-mephenytoin
    DEX
    dexamethasone
    CHLOR
    chlorzoxazone
    HLM
    human liver microsomes
    • Received March 26, 1998.
    • Accepted June 23, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

The Role of CYP2C in the In Vitro Bioactivation of the Contraceptive Steroid Desogestrel

Daniela M. Gentile, Carole H. J. Verhoeven, Tsutomu Shimada and David J. Back
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 975-982;

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Research ArticleArticle

The Role of CYP2C in the In Vitro Bioactivation of the Contraceptive Steroid Desogestrel

Daniela M. Gentile, Carole H. J. Verhoeven, Tsutomu Shimada and David J. Back
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 975-982;
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