PMID- 26772815
OWN - NLM
STAT- MEDLINE
DCOM- 20161111
LR  - 20161230
IS  - 1096-1186 (Electronic)
IS  - 1043-6618 (Linking)
VI  - 105
DP  - 2016 Mar
TI  - CYP1B1 inhibition attenuates doxorubicin-induced cardiotoxicity through a 
      mid-chain HETEs-dependent mechanism.
PG  - 28-43
LID - S1043-6618(15)30019-0 [pii]
LID - 10.1016/j.phrs.2015.12.016 [doi]
AB  - 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-kappaB (NF-kappaB). In 
      conclusion, our study provides the first evidence that the inhibition of CYP1B1 
      and mid-chain HETE formation attenuate DOX-induced cardiotoxicity.
CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
FAU - Maayah, Zaid H
AU  - Maayah ZH
AD  - Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for 
      Pharmacy and Health Research, T6G 2E1, University of Alberta, Edmonton, Canada.
FAU - Althurwi, Hassan N
AU  - Althurwi HN
AD  - Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for 
      Pharmacy and Health Research, T6G 2E1, University of Alberta, Edmonton, Canada.
FAU - Abdelhamid, Ghada
AU  - Abdelhamid G
AD  - 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.
FAU - Lesyk, Gabriela
AU  - Lesyk G
AD  - Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for 
      Pharmacy and Health Research, T6G 2E1, University of Alberta, Edmonton, Canada.
FAU - Jurasz, Paul
AU  - Jurasz P
AD  - Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for 
      Pharmacy and Health Research, T6G 2E1, University of Alberta, Edmonton, Canada.
FAU - El-Kadi, Ayman O S
AU  - El-Kadi AO
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160106
PL  - Netherlands
TA  - Pharmacol Res
JT  - Pharmacological research
JID - 8907422
RN  - 0 (2,4,3',5'-tetramethoxystilbene)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hydroxyeicosatetraenoic Acids)
RN  - 0 (Stilbenes)
RN  - 80168379AG (Doxorubicin)
RN  - EC 1.14.14.1 (Cyp1b1 protein, rat)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1B1)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/*toxicity
MH  - Cardiotoxicity/*drug therapy/metabolism/pathology
MH  - Cell Line
MH  - Cytochrome P-450 CYP1B1/*antagonists & inhibitors/metabolism
MH  - Doxorubicin/*toxicity
MH  - Enzyme Inhibitors/*therapeutic use
MH  - Humans
MH  - Hydroxyeicosatetraenoic Acids/*metabolism
MH  - Male
MH  - Myocardium/metabolism/pathology
MH  - Rats, Sprague-Dawley
MH  - Stilbenes/*therapeutic use
OTO - NOTNLM
OT  - Cytochrome P450
OT  - Doxorubicin
OT  - Mid-chain hydroxyeicosatetraenoic acids
EDAT- 2016/01/17 06:00
MHDA- 2016/11/12 06:00
CRDT- 2016/01/17 06:00
PHST- 2015/09/11 00:00 [received]
PHST- 2015/12/01 00:00 [revised]
PHST- 2015/12/15 00:00 [accepted]
PHST- 2016/01/17 06:00 [entrez]
PHST- 2016/01/17 06:00 [pubmed]
PHST- 2016/11/12 06:00 [medline]
AID - S1043-6618(15)30019-0 [pii]
AID - 10.1016/j.phrs.2015.12.016 [doi]
PST - ppublish
SO  - Pharmacol Res. 2016 Mar;105:28-43. doi: 10.1016/j.phrs.2015.12.016. Epub 2016 Jan 
      6.