title: CYP1B1 inhibition attenuates doxorubicin-induced cardiotoxicity through a mid-chain HETEs-dependent mechanism.
abstract: Doxorubicin (DOX) has been reported to be a very potent and effective anticancer agent. However, clinical treatment with DOX has been greatly limited due to its cardiotoxicity. Furthermore, several studies have suggested a role for cytochrome P450 1B1 (CYP1B1) and mid-chain hydroxyeicosatetraenoic acids (mid-chain HETEs) in DOX-induced cardiac toxicity. Therefore, we hypothesized that DOX induced cardiotoxicity is mediated through the induction of CYP1B1 and its associated mid-chain HETEs metabolite. To test our hypothesis, Sprague-Dawley rats and RL-14 cells were treated with DOX in the presence and absence of 2,3',4,5'-tetramethoxystilbene (TMS), a selective CYP1B1 inhibitor. Thereafter, cardiotoxicity parameters were determined using echocardiography, histopathology, and gene expression. Further, the level of mid-chain HETEs was quantified using liquid chromatography-electron spray ionization-mass spectrometry. Our results showed that DOX induced cardiotoxicity in vivo and in vitro as evidenced by deleterious changes in echocardiography, histopathology, and hypertrophic markers. Importantly, the TMS significantly reversed these changes. Moreover, the DOX-induced cardiotoxicity was associated with a proportional increase in the formation of cardiac mid-chain HETEs both in vivo and in our cell culture model. Interestingly, the inhibition of cardiotoxicity by TMS was associated with a dramatic decrease in the formation of cardiac mid-chain HETEs suggesting a mid-chain HETEs-dependent mechanism. Mechanistically, the protective effect of TMS against DOX-induced cardiotoxicity was mediated through the inhibition of mitogen activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). In conclusion, our study provides the first evidence that the inhibition of CYP1B1 and mid-chain HETE formation attenuate DOX-induced cardiotoxicity.
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for Pharmacy and Health Research, T6G 2E1, University of Alberta, Edmonton, Canada.
authors.forename: Zaid H
authors.initials: ZH
authors.lastname: Maayah
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for Pharmacy and Health Research, T6G 2E1, University of Alberta, Edmonton, Canada.
authors.forename: Hassan N
authors.initials: HN
authors.lastname: Althurwi
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for Pharmacy and Health Research, T6G 2E1, University of Alberta, Edmonton, Canada; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Egypt.
authors.forename: Ghada
authors.initials: G
authors.lastname: Abdelhamid
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for Pharmacy and Health Research, T6G 2E1, University of Alberta, Edmonton, Canada.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Lesyk
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for Pharmacy and Health Research, T6G 2E1, University of Alberta, Edmonton, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Jurasz
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for Pharmacy and Health Research, T6G 2E1, University of Alberta, Edmonton, Canada. Electronic address: aelkadi@ualberta.ca.
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D066126:Cardiotoxicity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D065633:Cytochrome P-450 CYP1B1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D013267:Stilbenes / Q000627:therapeutic use*
chemical_list: C440850:2,4,3',5'-tetramethoxystilbene; D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D013267:Stilbenes; D004317:Doxorubicin; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1
keywords: Cytochrome P450; Doxorubicin; Mid-chain hydroxyeicosatetraenoic acids