Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone

@article{Korhonen2008IdentificationOT,
  title={Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone},
  author={Tuomas Korhonen and Miia Turpeinen and Ari Tolonen and Kari Laine and Olavi Pelkonen},
  journal={The Journal of Steroid Biochemistry and Molecular Biology},
  year={2008},
  volume={110},
  pages={56-66}
}
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… Expand
A cocktail approach for assessing the in vitro activity of human cytochrome P450s: an overview of current methodologies.
TLDR
This article considers the probe reaction selections for each CYP according to regulatory recommendations, probe metabolic properties, probe concentrations and analytical sensitivity, but it also highlights a challenge specific to cocktail design, which is probe-probe interaction. Expand
Interactions between human cytochrome P450 enzymes and steroids: physiological and pharmacological implications
TLDR
This article summarizes the current understanding of the ability of steroids to act as substrates, inhibitors or heteroactivators for human CYP enzymes, with a specific focus on their functional consequences. Expand
Selective whole-cell biosynthesis of the designer drug metabolites 15- or 16-betahydroxynorethisterone by engineered Cytochrome P450 BM3 mutants
Abstract In the present study, the whole-cell biotransformation using strains expressing CYP BM3 mutants has been evaluated for the stereoselective hydroxylation of the steroid norethisterone (NET),Expand
Chapter 6 Selective whole-cell biosynthesis of the designer drug metabolites 15-or 16-β-hydroxynorethisterone by engineered cytochrome P 450 BM 3 mutants
  • 2015
In the present study, the whole-cell biotransformation using strains expressing CYP BM3 mutants has been evaluated for the stereoselective hydroxylation of the steroid norethisterone (NET), a widelyExpand
Clinical drug‐drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P‐glycoprotein
TLDR
Caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P‐gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin. Expand
Prediction of regioselectivity and preferred order of metabolisms on CYP1A2-mediated reactions. Part 2: Solving substrate interactions of CYP1A2 with non-PAH substrates on the template system.
TLDR
Present CYP1A2 Template system offers a unified evaluation of human CYP2A2 ligands, which aids for toxicological assessments as well as drug metabolism studies, irrespective of their shapes and flexibilities. Expand
Determination and identification of estrogenic compounds generated with biosynthetic enzymes using hyphenated screening assays, high resolution mass spectrometry and off-line NMR.
TLDR
The multi-target screening approach combined with full structure characterization based on high resolution MS(/MS) and NMR spectroscopy demonstrated in this paper can generally be applied to e.g. metabolism studies and compound-library screening. Expand
Involvement of cytochrome P450 enzymes in inflammation and cancer: a review
TLDR
The relevance of CYPs in hepatocarcinoma, breast cancer, lung cancer, and chemotherapy is reviewed by reviewing in vitro, in vivo, and clinical studies, and the importance of elucidating the relationships between inflammation, CYPs, and cancer to predict drug interactions and therapeutic efficacy is discussed. Expand
Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir
TLDR
Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy and does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Expand
The Influence of in Vitro Gill and Liver Metabolism of Xenobiotics on Fish Bioconcentration
TLDR
Studies indicate that the inclusion of kM in BCF models can bring predicted bioconcentration estimates closer to in vivo values, and support CYP1A2 as an alternative metabolic pathway. Expand
...
1
2
3
4
...

References

SHOWING 1-10 OF 48 REFERENCES
In vitro inhibition of cytochrome P450 enzymes in human liver microsomes by a potent CYP2A6 inhibitor, trans-2-phenylcyclopropylamine (tranylcypromine), and its nonamine analog, cyclopropylbenzene.
TLDR
Results suggest that tranylcypromine seems an adequately selective CYP2A6 inhibitor for in vitro use and may have at least two P450-related binding sites in liver microsomes. Expand
Selective inhibition of CYP2B6-catalyzed bupropion hydroxylation in human liver microsomes in vitro.
TLDR
ThioTEPA is a drug of choice when high CYP2B6 selectivity among major P450 enzymes is required and ticlopidine is a useful alternative under a controlled experimental setup and when higher potency is needed. Expand
Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes.
TLDR
Results suggest that miconazole is the strongest inhibitor of CYP2C9 and CYP3A4, followed by voriconazoles and fluconazole, whereas micafungin would not cause clinically significant interactions with other drugs that are metabolized by CYP 2C9 or CYP1C19 via the inhibition of metabolism. Expand
A screening study on the liability of eight different female sex steroids to inhibit CYP2C9, 2C19 and 3A4 activities in human liver microsomes.
TLDR
The liability of clinically used female sex steroids to inhibit CYP2C9, 2C19 and 3A4 activities in human liver microsomes is very distinctive and these differences among both the oestrogen and progestin hormones may, at least in part, explain the variable results from clinical trials examining inhibitory effects of hormone replacement therapy and oral contraceptives on drug metabolism. Expand
Role of CYP2C9 polymorphism in losartan oxidation.
TLDR
In vitro results indicate that CYP2C9 is the major human P450 isoenzyme responsible for losartan oxidation and that the CYP1C9 genotype contributes to interindividual differences in losarta oxidation and activation. Expand
Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies.
TLDR
The prediction generated from these studies, that fluconazole is a potent in vivo inhibitor of warfarin metabolism, is tested in complementary studies reported in the accompanying article, "Warfarin-Fluconazoles II". Expand
Formation of (R)-8-hydroxywarfarin in human liver microsomes. A new metabolic marker for the (S)-mephenytoin hydroxylase, P4502C19.
TLDR
Kinetic studies demonstrate that two forms of human liver cytochrome P450 are responsible for the formation of (R)-8-hydroxywarfarin and (S)-mephenytoin, and a high-affinity enzyme is identified as P4502C19 on the basis of the following evidence. Expand
Multiple P450 substrates in a single run: rapid and comprehensive in vitro interaction assay.
TLDR
The cocktail developed is suitable for fast and reliable in vitro screening of the interaction potential and characteristics of NCEs and assessed with cDNA expressed P450s and diagnostic CYP-specific inhibitors. Expand
In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines.
TLDR
Although the competitive inhibition between some sulphonamides and tolbutamide is consistent with metabolism by the same isozyme of cytochrome P-450 it does not prove it and further studies with purified enzymes will be necessary to confirm this. Expand
Cytochrome P450 (CYP) inhibition screening: comparison of three tests.
  • M. Turpeinen, L. E. Korhonen, +4 authors O. Pelkonen
  • Chemistry, Medicine
  • European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
  • 2006
TLDR
Three different types of cytochrome P450 inhibition tests are compared: the traditional single substrate assays, the fluorescent probe method with recombinant human CYPs, and a novel n-in-one technique. Expand
...
1
2
3
4
5
...