William R. Arnold, Javier L. Baylon, Emad Tajkhorshid, and Aditi Das.
Arachidonic acid metabolism by human cardiovascular CYP2J2 is
modulated by doxorubicin.
Biochemistry, 56:6700-6712, 2017.
(PMC: PMC5743546)
ARNO2017-ET
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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