bi7b01025_si_003.avi (1.33 MB)
Arachidonic Acid Metabolism by Human Cardiovascular CYP2J2 Is Modulated by Doxorubicin
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posted on 2017-12-04, 00:00 authored by William
R. Arnold, Javier L. Baylon, Emad Tajkhorshid, Aditi DasDoxorubicin
(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.