Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity.
Human cytochrome P-450 (CYP)2J2 is abundant in heart and active in biosynthesis of epoxyeicosatrienoic acids (EETs). Recently, we demonstrated that these eicosanoid products protect myocardium from ischemia-reperfusion injury. The present study utilized transgenic (Tr) mice with cardiomyocyte-specific overexpression of human CYP2J2 to investigate protection toward toxicity resulting from acute (0, 5, or 15 mg/kg daily for 3 days, followed by 24-h recovery) or chronic (0, 1.5, or 3.0 mg/kg biweekly for 5 wk, followed by 2-wk recovery) doxorubicin (Dox) administration. Acute treatment resulted in marked elevations of serum lactate dehydrogenase and creatine kinase levels that were significantly greater in wild-type (WT) than CYP2J2 Tr mice. Acute treatment also resulted in less activation of stress response enzymes in CYP2J2 Tr mice (catalase 750% vs. 300% of baseline, caspase-3 235% vs. 165% of baseline in WT vs. CYP2J2 Tr mice). Moreover, CYP2J2 Tr hearts exhibited less Dox-induced cardiomyocytes apoptosis (measured by TUNEL) compared with WT hearts. After chronic treatment, comparable decreases in body weight were observed in WT and CYP2J2 Tr mice. However, cardiac function, assessed by measurement of fractional shortening with M-mode transthoracic echocardiography, was significantly higher in CYP2J2 Tr than WT hearts after chronic Dox treatment (WT 37 +/- 2%, CYP2J2 Tr 47 +/- 1%). WT mice also had larger increases in beta-myosin heavy chain and cardiac ankryin repeat protein compared with CYP2J2 Tr mice. CYP2J2 Tr hearts had a significantly higher rate of Dox metabolism than WT hearts (2.2 +/- 0.25 vs. 1.6 +/- 0.50 ng.min(-1).100 microg protein(-1)). In vitro data from H9c2 cells demonstrated that EETs attenuated Dox-induced mitochondrial damage. Together, these data suggest that cardiac-specific overexpression of CYP2J2 limited Dox-induced toxicity.
Zhang
Yunfang
Y
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
El-Sikhry
Haitham
H
Chaudhary
Ketul R
KR
Batchu
Sri Nagarjun
SN
Shayeganpour
Anooshirvan
A
Jukar
Taibeh Orujy
TO
Bradbury
J Alyce
JA
Graves
Joan P
JP
DeGraff
Laura M
LM
Myers
Page
P
Rouse
Douglas C
DC
Foley
Julie
J
Nyska
Abraham
A
Zeldin
Darryl C
DC
Seubert
John M
JM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D015415:Biomarkers; D003402:Creatine Kinase / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004452:Echocardiography; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology*; D006334:Heart Function Tests; D006801:Humans; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; C000717350:CYP2J2 protein, human; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D007770:L-Lactate Dehydrogenase; D000090762:Cytochrome P-450 CYP2J2; D003402:Creatine Kinase