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Arachidonic Acid Metabolism by Human Cardiovascular CYP2J2 Is Modulated by Doxorubicin
- Source :
- Biochemistry. 56:6700-6712
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
Abstract
- Doxorubicin (DOX) is a chemotherapeutic that is used in the treatment of a wide variety of cancers. However, it causes cardiotoxicity partly due to the formation of reactive oxygen species (ROS). CYP2J2 is a human cytochrome P450 that is highly 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 (CPR), 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 change in the ratio of the EET regioisomers. Furthermore, molecular dynamics (MD) 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 see if these observations are unique to DOX/7-de-aDOX, we use non-cardiotoxic DOX analogues, zorubicin (ZRN) and 5-iminodaunorubicin (IDN). ZRN and 5-IDN inhibit CYP2J2-mediated AA metabolism, but does not change the ratio of EET regioisomers. Taken together, 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.
- Subjects :
- 0301 basic medicine
Metabolite
Fluorescence Polarization
Molecular Dynamics Simulation
Cytochrome P-450 CYP2J2
Biochemistry
Article
CYP2J2
03 medical and health sciences
chemistry.chemical_compound
Cytochrome P-450 Enzyme System
Catalytic Domain
polycyclic compounds
medicine
Humans
Doxorubicin
chemistry.chemical_classification
Reactive oxygen species
Antibiotics, Antineoplastic
Arachidonic Acid
030102 biochemistry & molecular biology
biology
Myocardium
Active site
Cytochrome P450 reductase
Stereoisomerism
Metabolism
Kinetics
030104 developmental biology
chemistry
Drug Design
biology.protein
Arachidonic acid
NADP
medicine.drug
Subjects
Details
- ISSN :
- 15204995 and 00062960
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Biochemistry
- Accession number :
- edsair.doi.dedup.....c7e0d9fc611313e92907863802b77f62
- Full Text :
- https://doi.org/10.1021/acs.biochem.7b01025