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Role of Cytochrome P450 2J2 and Soluble Epoxide Hydrolase in Drug Cardiotoxicity
Author(s) -
Solanki Meetal Satishkumar,
Jones Barry,
DawkinsHall Laurence,
Pointon Amy,
Herbert Karl
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.561.14
Subject(s) - epoxide hydrolase 2 , cardiotoxicity , astemizole , pharmacology , chemistry , cytochrome p450 , epoxide hydrolase , umbilical vein , in vivo , biochemistry , in vitro , enzyme , toxicity , medicine , biology , microsome , microbiology and biotechnology , organic chemistry
Cytochrome P450 2J2 (CYP2J2), a multifunctional enzyme that is abundant in cardiac tissue, metabolises endogenous arachidonic acid to epoxyeicosatrienoic acids (EETs) which protect the heart. EETs dilate blood vessels increasing blood flow to heart muscle cells, and reduce inflammation which may protect against development of coronary artery disease. Moreover, it is reported that EETs mitigate the harmful effects of the cancer chemotherapeutic drug, doxorubicin, which causes cardiotoxicity in some patients. In vivo, EETs are rapidly metabolised by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs) which are less biologically active. Several studies have shown that sEH may play an influential role in the development of atherosclerosis and cardiovascular disease, however, its role in cardiotoxicity has not been well reported. The current study aimed to investigate in vitro the role of EETs in the cardiotoxicity of a drug known to interact with CYP2J2, astemizole. Human cardiac myocytes (HCM) and human umbilical vein endothelial cell‐derived EA.hy926 cells, were incubated with astemizole in the absence or presence of inhibitors which were hypothesised to either enhance or diminish EET production. Changes to gene and protein expression were determined and toxicity was assessed. mRNA and protein expression of CYP2J2 and sEH was established in both cell models with higher expression in HCM in line with literature reports. Investigation of sEH expression showed the apparent presence of multiple mRNA isoforms but the predominant isoform was assessed. Treatment of cells with astemizole showed a toxic effect in both cell types accompanied by increased mRNA expression of sEH and CYP2J2 in EA.hy926 cells and HCM. Addition of the sEH inhibitor trans ‐4‐[4‐3‐adamantan‐1‐yl‐ureido)‐cyclohexyloxyl]‐benzoic acid, (t‐AUCB), which increases levels of EETs in cells and exogenous 11,12‐EET protected cells against the damaging effects of six hours exposure to astemizole. In response to t‐AUCB in astemizole treated cells sEH expression was increased and CYP2J2 mRNA and protein was decreased; presumably a feedback mechanism exists following sEH inhibition that involves both CYP2J2 and sEH. Taken together, these data show that enhancing EET levels protected against astemizole toxicity in cardiovascular cells in vitro , indicating that the balance between endogenous CYP2J2 and sEH activities may play key role in counteracting damage to the heart by certain drugs. Agents that promote EETs in the heart may be useful adjuncts to counteract the cardiotoxicity due to certain drugs. Support or Funding Information This research was supported by Biotechnology and Biosciences Research Council, UK (ref: BB/M503368/1) and AstraZeneca. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .