TY - JOUR
T1 - Anthracycline derivatives inhibit cardiac CYP2J2
AU - Kim, Justin S.
AU - Arango, Andres S.
AU - Shah, Swapnil
AU - Arnold, William R.
AU - Tajkhorshid, Emad
AU - Das, Aditi
N1 - This research was supported by American Heart Association Scientist Development Grant 15SDG25760064 (A.D.) and by National Institutes of Health Grants R01 GM1155884 (A.D.) and in part by the National Institutes of Health R01-GM101048, U54-GM087519, and P41-GM104601–31 (E.T.). E.T. acknowledges computing resources provided by Blue Waters at National Center for Supercomputing Applications. All simulations have been performed using XSEDE resources (grant MCA06N060 to ET).
This research was supported by American Heart Association Scientist Development Grant 15SDG25760064 (A.D.) and by National Institutes of Health Grants R01 GM1155884 (A.D.) and in part by the National Institutes of Health R01-GM101048 , U54-GM087519 , and P41-GM104601–31 (E.T.). E.T. acknowledges computing resources provided by Blue Waters at National Center for Supercomputing Applications. All simulations have been performed using XSEDE resources (grant MCA06N060 to ET).
PY - 2022/4
Y1 - 2022/4
N2 - Anthracycline chemotherapeutics are highly effective, but their clinical usefulness is hampered by adverse side effects such as cardiotoxicity. Cytochrome P450 2J2 (CYP2J2) is a cytochrome P450 epoxygenase in human cardiomyocytes that converts arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acid (EET) regioisomers. Herein, we performed biochemical studies to understand the interaction of anthracycline derivatives (daunorubicin, doxorubicin, epirubicin, idarubicin, 5-iminodaunorubicin, zorubicin, valrubicin, and aclarubicin) with CYP2J2. We utilized fluorescence polarization (FP) to assess whether anthracyclines bind to CYP2J2. We found that aclarubicin bound the strongest to CYP2J2 despite it having large bulky groups. We determined that ebastine competitively inhibits anthracycline binding, suggesting that ebastine and anthracyclines may share the same binding site. Molecular dynamics and ensemble docking revealed electrostatic interactions between the anthracyclines and CYP2J2, contributing to binding stability. In particular, the glycosamine groups in anthracyclines are stabilized by binding to glutamate and aspartate residues in CYP2J2 forming salt bridge interactions. Furthermore, we used iterative ensemble docking schemes to gauge anthracycline influence on EET regioisomer production and anthracycline inhibition on AA metabolism. This was followed by experimental validation of CYP2J2-mediated metabolism of anthracycline derivatives using liquid chromatography tandem mass spectrometry fragmentation analysis and inhibition of CYP2J2-mediated AA metabolism by these derivatives. Taken together, we use both experimental and theoretical methodologies to unveil the interactions of anthracycline derivatives with CYP2J2. These studies will help identify alternative mechanisms of how anthracycline cardiotoxicity may be mediated through the inhibition of cardiac P450, which will aid in the design of new anthracycline derivatives with lower toxicity.
AB - Anthracycline chemotherapeutics are highly effective, but their clinical usefulness is hampered by adverse side effects such as cardiotoxicity. Cytochrome P450 2J2 (CYP2J2) is a cytochrome P450 epoxygenase in human cardiomyocytes that converts arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acid (EET) regioisomers. Herein, we performed biochemical studies to understand the interaction of anthracycline derivatives (daunorubicin, doxorubicin, epirubicin, idarubicin, 5-iminodaunorubicin, zorubicin, valrubicin, and aclarubicin) with CYP2J2. We utilized fluorescence polarization (FP) to assess whether anthracyclines bind to CYP2J2. We found that aclarubicin bound the strongest to CYP2J2 despite it having large bulky groups. We determined that ebastine competitively inhibits anthracycline binding, suggesting that ebastine and anthracyclines may share the same binding site. Molecular dynamics and ensemble docking revealed electrostatic interactions between the anthracyclines and CYP2J2, contributing to binding stability. In particular, the glycosamine groups in anthracyclines are stabilized by binding to glutamate and aspartate residues in CYP2J2 forming salt bridge interactions. Furthermore, we used iterative ensemble docking schemes to gauge anthracycline influence on EET regioisomer production and anthracycline inhibition on AA metabolism. This was followed by experimental validation of CYP2J2-mediated metabolism of anthracycline derivatives using liquid chromatography tandem mass spectrometry fragmentation analysis and inhibition of CYP2J2-mediated AA metabolism by these derivatives. Taken together, we use both experimental and theoretical methodologies to unveil the interactions of anthracycline derivatives with CYP2J2. These studies will help identify alternative mechanisms of how anthracycline cardiotoxicity may be mediated through the inhibition of cardiac P450, which will aid in the design of new anthracycline derivatives with lower toxicity.
KW - Anthracycline
KW - Arachidonic acid
KW - CYP2J2
KW - Cardiotoxicity
KW - Doxorubicin
KW - Epoxyeicosatrienoic acid
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UR - http://www.scopus.com/inward/citedby.url?scp=85123258496&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2022.111722
DO - 10.1016/j.jinorgbio.2022.111722
M3 - Article
C2 - 35078036
AN - SCOPUS:85123258496
SN - 0162-0134
VL - 229
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
M1 - 111722
ER -