Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone.
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Korhonen T, Turpeinen M, Tolonen A, Laine K, Pelkonen O
Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone.
J Steroid Biochem Mol Biol. 2008 May;110(1-2):56-66. doi: 10.1016/j.jsbmb.2007.09.025. Epub 2008 Feb 15.
- PubMed ID
- 18356043 [ View in PubMed]
- Abstract
This study examined the cytochrome P450 (CYP) enzyme selectivity of in vitro bioactivation of lynestrenol to norethindrone and the further metabolism of norethindrone. Screening with well-established chemical inhibitors showed that the formation of norethindrone was potently inhibited by CYP3A4 inhibitor ketoconazole (IC(50)=0.02 microM) and with CYP2C9 inhibitor sulphaphenazole (IC(50)=2.13 microM); the further biotransformation of norethindrone was strongly inhibited by ketoconazole (IC(50)=0.09 microM). Fluconazole modestly inhibited both lynestrenol bioactivation and norethindrone biotransformation. Lynestrenol bioactivation was mainly catalysed by recombinant human CYP2C9, CYP2C19 and CYP3A4; rCYP3A4 was responsible for the hydroxylation of norethindrone. A significant correlation was observed between norethindrone formation and tolbutamide hydroxylation, a CYP2C9-selective activity (r=0.63; p=0.01). Norethindrone hydroxylation correlated significantly with model reactions of CYP2C19 and CYP3A4. The greatest immunoinhibition of lynestrenol bioactivation was seen in incubations with CYP2C-Ab. The CYP3A4-Ab reduced norethindrone hydroxylation by 96%. Both lynestrenol and norethindrone were weak inhibitors of CYP2C9 (IC(50) of 32 microM and 46 microM for tolbutamide hydroxylation, respectively). In conclusion, CYP2C9, CYP2C19 and CYP3A4 are the primary cytochromes in the bioactivation of lynestrenol in vitro, while CYP3A4 catalyses the further metabolism of norethindrone.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Lynestrenol Cytochrome P450 2C19 Protein Humans NoSubstrateInhibitorDetails Lynestrenol Cytochrome P450 2C9 Protein Humans NoSubstrateDetails Lynestrenol Cytochrome P450 3A4 Protein Humans NoSubstrateDetails Norethisterone Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Norethisterone Cytochrome P450 2A6 Protein Humans UnknownSubstrateDetails Norethisterone Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareNorethisteroneVoriconazole The serum concentration of Norethisterone can be increased when it is combined with Voriconazole.
