ArticleBiochemistry2017
Arachidonic Acid Metabolism by Human Cardiovascular CYP2J2 Is Modulated by Doxorubicin.
Article in Biochemistry, 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, 35 citations in OpenAlex.
- Elucidating the binding and metabolic interactions of sunitinib and sorafenib with Cytochrome P450s CYP2U1 and CYP2D6.Molecular pharmacology · 2026Article
- Construction of a CYP2J2-Template System and Its Application for Ligand Metabolism Prediction.Food safety (Tokyo, Japan) · 2024Article
- Elucidating the Mechanism of Metabolism of Cannabichromene by Human Cytochrome P450s.Journal of natural products · 2024Article
- Functional Validation of Doxorubicin-Induced Cardiotoxicity-Related Genes.JACC. CardioOncology · 2024Article
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- Anthracycline derivatives inhibit cardiac CYP2J2.Journal of inorganic biochemistry · 2022Article
- Differential Interactions of Selected Phytocannabinoids with Human CYP2D6 Polymorphisms.Biochemistry · 2021Article
- Extrahepatic cytochrome P450 epoxygenases: pathophysiology and clinical significance in human gastrointestinal cancers.Oncotarget · 2021Review
- Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel.Nature communications · 2021Article
- CYP2J2 Molecular Recognition: A New Axis for Therapeutic Design.Pharmacology & therapeutics · 2020Review
- A Targeted Metabolomics-Based Assay Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Identifies Structural and Functional Cardiotoxicity Potential.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- Polymorphisms of CYP2C8 Alter First-Electron Transfer Kinetics and Increase Catalytic Uncoupling.International journal of molecular sciences · 2019Article
- Role of Arginine 117 in Substrate Recognition by Human Cytochrome P450 2J2.International journal of molecular sciences · 2018Article
- Cross-talk of cannabinoid and endocannabinoid metabolism is mediated via human cardiac CYP2J2.Journal of inorganic biochemistry · 2018Article
- Regulation of CYP2J2 and EET Levels in Cardiac Disease and Diabetes.International journal of molecular sciences · 2018Review
- An Emerging Pathway of Doxorubicin Cardiotoxicity Mediated through CYP2J2.Biochemistry · 2018Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Doxorubicin (DOX) is a chemotherapeutic that is used in the treatment of a wide variety of cancers. However, it causes cardiotoxicity partly because of the formation of reactive oxygen species. CYP2J2 is a human cytochrome P450 that is strongly expressed in cardiomyocytes. It converts arachidonic acid (AA) into four different regioisomers of epoxyeicosatrienoic acids (EETs). Using kinetic analyses, we show that AA metabolism by CYP2J2 is modulated by DOX. We show that cytochrome P450 reductase, the redox partner of CYP2J2, metabolizes DOX to 7-deoxydoxorubicin aglycone (7-de-aDOX). This metabolite then binds to CYP2J2 and inhibits and alters the preferred site of metabolism of AA, leading to a change in the ratio of the EET regioisomers. Furthermore, molecular dynamics simulations indicate that 7-de-aDOX and AA can concurrently bind to the CYP2J2 active site to produce these changes in the site of AA metabolism. To determine if these observations are unique to DOX/7-de-aDOX, we use noncardiotoxic DOX analogues, zorubicin (ZRN) and 5-iminodaunorubicin (5-IDN). ZRN and 5-IDN inhibit CYP2J2-mediated AA metabolism but do not change the ratio of EET regioisomers. Altogether, we demonstrate that DOX and 7-de-aDOX inhibit CYP2J2-mediated AA metabolism and 7-de-aDOX binds close to the active site to alter the ratio of cardioprotective EETs. These mechanistic studies of CYP2J2 can aid in the design of new alternative DOX derivatives.
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Registered trials
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