ArticleThe Biochemical journal2017
Toward a systems approach to the human cytochrome P450 ensemble: interactions between CYP2D6 and CYP2E1 and their functional consequences.
Article in The Biochemical journal, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- Non-additivity of the functional properties of individual P450 species and its manifestation in the effects of alcohol consumption on the metabolism of ketamine and amitriptyline.Biochemical pharmacology · 2024Article
- Functional characterization of CYP1 enzymes: Complex formation, membrane localization and function.Journal of inorganic biochemistry · 2023Article
- Exploring the Interactome of Cytochrome P450 2E1 in Human Liver Microsomes with Chemical Crosslinking Mass Spectrometry.Biomolecules · 2022Article
- Assembling the P450 puzzle: on the sources of nonadditivity in drug metabolism.Trends in pharmacological sciences · 2021Review
- Complex Cytochrome P450 Kinetics Due to Multisubstrate Binding and Sequential Metabolism. Part 1. Theoretical Considerations.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- Probing functional interactions between cytochromes P450 with principal component analysis of substrate saturation profiles and targeted proteomics.Archives of biochemistry and biophysics · 2021Article
- Identification of the contact region responsible for the formation of the homomeric CYP1A2•CYP1A2 complex.The Biochemical journal · 2021Article
- Effects of alcohol-induced increase in CYP2E1 content in human liver microsomes on the activity and cooperativity of CYP3A4.Archives of biochemistry and biophysics · 2021Article
- Heteromeric complex formation between human cytochrome P450 CYP1A1 and heme oxygenase-1.The Biochemical journal · 2021Article
- Multienzyme Kinetics and Sequential Metabolism.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Variability in Human In Vitro Enzyme Kinetics.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Nonadditivity in human microsomal drug metabolism revealed in a study with coumarin 152, a polyspecific cytochrome P450 substrate.Xenobiotica; the fate of foreign compounds in biological systems · 2020Article
- Mechanisms of Herb-Drug Interactions Involving Cinnamon and CYP2A6: Focus on Time-Dependent Inhibition by Cinnamaldehyde and 2-Methoxycinnamaldehyde.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Toward a systems approach to cytochrome P450 ensemble: interactions of CYP2E1 with other P450 species and their impact on CYP1A2.The Biochemical journal · 2019Article
- Impact of Lipid Partitioning on the Design, Analysis, and Interpretation of Microsomal Time-Dependent Inactivation.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Kinetic mechanism of time-dependent inhibition of CYP2D6 by 3,4-methylenedioxymethamphetamine (MDMA): Functional heterogeneity of the enzyme and the reversibility of its inactivation.Biochemical pharmacology · 2018Article
- Comprehensive integrated analysis of gene expression datasets identifies key anti-cancer targets in different stages of breast cancer.Experimental and therapeutic medicine · 2018Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Functional cross-talk among human drug-metabolizing cytochrome P450 through their association is a topic of emerging importance. Here, we studied the interactions of human CYP2D6, a major metabolizer of psychoactive drugs, with one of the most prevalent human P450 enzymes, ethanol-inducible CYP2E1. Detection of P450-P450 interactions was accomplished through luminescence resonance energy transfer between labeled proteins incorporated into human liver microsomes and the microsomes of insect cells containing NADPH-cytochrome P450 reductase. The potential of CYP2D6 to form oligomers in the microsomal membrane is among the highest observed with human cytochrome P450 studied up to date. We also observed the formation of heteromeric complexes of CYP2D6 with CYP2E1 and CYP3A4, and found a significant modulation of these interactions by 3,4-methylenedioxymethylamphetamine, a widespread drug of abuse metabolized by CYP2D6. Our results demonstrate an ample alteration of the catalytic properties of CYP2D6 and CYP2E1 caused by their association. In particular, we demonstrated that preincubation of microsomes containing co-incorporated CYP2D6 and CYP2E1 with CYP2D6-specific substrates resulted in considerable time-dependent activation of CYP2D6, which presumably occurs via a slow substrate-induced reorganization of CYP2E1-CYP2D6 hetero-oligomers. Furthermore, we demonstrated that the formation of heteromeric complexes between CYP2E1 and CYP2D6 affects the stoichiometry of futile cycling and substrate oxidation by CYP2D6 by means of decreasing the electron leakage through the peroxide-generating pathways. Our results further emphasize the role of P450-P450 interactions in regulatory cross-talk in human drug-metabolizing ensemble and suggest a role of interactions of CYP2E1 with CYP2D6 in pharmacologically important instances of alcohol-drug interactions.
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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.