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The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel.
J Pharmacol Exp Ther 1998; 287(3):975-82JP

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.

Authors+Show Affiliations

Department of Pharmacology and Therapeutics, New Medical Building, Liverpool, L69 3GE, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9864282

Citation

Gentile, D M., et al. "The Role of CYP2C in the in Vitro Bioactivation of the Contraceptive Steroid Desogestrel." The Journal of Pharmacology and Experimental Therapeutics, vol. 287, no. 3, 1998, pp. 975-82.
Gentile DM, Verhoeven CH, Shimada T, et al. The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel. J Pharmacol Exp Ther. 1998;287(3):975-82.
Gentile, D. M., Verhoeven, C. H., Shimada, T., & Back, D. J. (1998). The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel. The Journal of Pharmacology and Experimental Therapeutics, 287(3), pp. 975-82.
Gentile DM, et al. The Role of CYP2C in the in Vitro Bioactivation of the Contraceptive Steroid Desogestrel. J Pharmacol Exp Ther. 1998;287(3):975-82. PubMed PMID: 9864282.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel. AU - Gentile,D M, AU - Verhoeven,C H, AU - Shimada,T, AU - Back,D J, PY - 1998/12/24/pubmed PY - 1998/12/24/medline PY - 1998/12/24/entrez KW - Biology KW - Clinical Research KW - Contraception KW - Contraceptive Agents KW - Contraceptive Agents, Female KW - Contraceptive Agents, Progestin KW - Desogestrel KW - Enzymes KW - Enzymes And Enzyme Inhibitors KW - Family Planning KW - In Vitro KW - Physiology KW - Research Methodology KW - Research Report SP - 975 EP - 82 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 287 IS - 3 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9864282/The_role_of_CYP2C_in_the_in_vitro_bioactivation_of_the_contraceptive_steroid_desogestrel_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9864282 DB - PRIME DP - Unbound Medicine ER -