CYP1B1 inhibition attenuates doxorubicin-induced cardiotoxicity through a mid-chain HETEs-dependent mechanism

Pharmacological Research : the Official Journal of the Italian Pharmacological Society
Zaid H MaayahAyman O S El-Kadi

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 t...Continue Reading

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Citations

Apr 25, 2017·Journal of Cardiovascular Pharmacology·Samya ElkhataliAyman O S El-Kadi
Dec 3, 2017·Cardiovascular Toxicology·Zaid H MaayahAyman O S El-Kadi
Feb 11, 2018·Scientific Reports·Zaid H MaayahAyman O S El-Kadi
Feb 7, 2019·Cardiovascular Research·Inbar Raber, Aarti Asnani
May 4, 2017·Drug Delivery and Translational Research·Samaa AlrushaidNeal M Davies
Dec 13, 2017·British Journal of Pharmacology·Mireille AlhouayekChristopher J Fowler
Mar 7, 2019·Journal of Cardiovascular Pharmacology·Eman SalahStevan P Tofovic
Dec 28, 2019·International Journal of Molecular Sciences·Stevan P Tofovic, Edwin K Jackson
Jun 22, 2020·Inflammopharmacology·Zaid H MaayahJason R B Dyck
Jan 13, 2017·Biology of Sex Differences·Marianne K O GrantBeshay N Zordoky
Jan 29, 2020·Antioxidants & Redox Signaling·Valentina SalaAlessandra Ghigo
Nov 14, 2020·Clinical Science·Alexa N CarreraBeshay N Zordoky
Jul 9, 2021·European Journal of Drug Metabolism and Pharmacokinetics·Sherif M ShoiebAyman O S El-Kadi

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