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.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Arnold WR,Baylon JL,Tajkhorshid E,Das Adoi
10.1021/acs.biochem.7b01025subject
Has Abstractpub_date
2017-12-26 00:00:00pages
6700-6712issue
51eissn
0006-2960issn
1520-4995journal_volume
56pub_type
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