ArticleBiochemistry2015
Mechanism of drug-drug interactions mediated by human cytochrome P450 CYP3A4 monomer.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
42 citing papers in PubMed, 66 citations in OpenAlex.
- A Novel Technology Platform for Extracellular Vesicle-Targeted Expression of Drug-Metabolizing Enzymes: Driving CYP3A4 Expression and Secretion via the EABR Motif.Biomedicines · 2026Article
- Integrated 3D-QSAR and cellular profiling of sulfated and hydrophobic aminoglycoside glycans to modulate heparanase activity.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Lipid Dependence of CYP3A4 Activity in Nanodiscs.Biology · 2026Article
- In silico molecular targets, docking, dynamics simulation and physiologically based pharmacokinetics modeling of oritavancin.BMC pharmacology & toxicology · 2024Article
- Improved Highly Mobile Membrane Mimetic Model for Investigating Protein-Cholesterol Interactions.Journal of chemical information and modeling · 2024Article
- Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity.Journal of xenobiotics · 2024Review
- A cytochrome P450 insecticide detoxification mechanism is not conserved across the Megachilidae family of bees.Evolutionary applications · 2024Article
- Factors influencing the detergent-free membrane protein isolation using synthetic nanodisc-forming polymers.Biochimica et biophysica acta. Biomembranes · 2024Article
- Article
- Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Structural Dynamics of Cytochrome P450 3A4 in the Presence of Substrates and Cytochrome P450 Reductase.Biochemistry · 2021Article
- Midazolam as a Probe for Drug-Drug Interactions Mediated by CYP3A4: Homotropic Allosteric Mechanism of Site-Specific Hydroxylation.Biochemistry · 2021Article
- Nanodiscs: A toolkit for membrane protein science.Protein science : a publication of the Protein Society · 2021Review
- CYP2J2 Molecular Recognition: A New Axis for Therapeutic Design.Pharmacology & therapeutics · 2020Review
- Dynamics and Location of the Allosteric Midazolam Site in Cytochrome P4503A4 in Lipid Nanodiscs.Biochemistry · 2020Article
- Differing Membrane Interactions of Two Highly Similar Drug-Metabolizing Cytochrome P450 Isoforms: CYP 2C9 and CYP 2C19.International journal of molecular sciences · 2019Article
- Biotransformation of the Mycotoxin Enniatin B1 by CYP P450 3A4 and Potential for Drug-Drug Interactions.Metabolites · 2019Article
- Correction to "Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213".Biochemistry · 2019Article
- Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213.Biochemistry · 2019Article
- Steroid bioconjugation to a CYP3A4 allosteric site and its effect on substrate binding and coupling efficiency.Archives of biochemistry and biophysics · 2018Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Using Nanodiscs, we quantitate the heterotropic interaction between two different drugs mediated by monomeric CYP3A4 incorporated into a nativelike membrane environment. The mechanism of this interaction is deciphered by global analysis of multiple-turnover experiments performed under identical conditions using the pure substrates progesterone (PGS) and carbamazepine (CBZ) and their mixtures. Activation of CBZ epoxidation and simultaneous inhibition of PGS hydroxylation are measured and quantitated through differences in their respective affinities for both a remote allosteric site and the productive catalytic site near the heme iron. Preferred binding of PGS at the allosteric site and a stronger preference for CBZ binding at the productive site give rise to a nontrivial drug-drug interaction. Molecular dynamics simulations indicate functionally important conformational changes caused by PGS binding at the allosteric site and by two CBZ molecules positioned inside the substrate binding pocket. Structural changes involving Phe-213, Phe-219, and Phe-241 are thought to be responsible for the observed synergetic effects and positive allosteric interactions between these two substrates. Such a mechanism is likely of general relevance to the mutual heterotropic effects caused by biologically active compounds that exhibit different patterns of interaction with the distinct allosteric and productive sites of CYP3A4, as well as other xenobiotic metabolizing cytochromes P450 that are also involved in drug-drug interactions. Importantly, this work demonstrates that a monomeric CYP3A4 can display the full spectrum of activation and cooperative effects that are observed in hepatic membranes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.