Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity.

Full Abstract

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.

Author information

Author/s: Zhang, Yunfang (Y); 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);

Affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.

Journal and publication information

Publication Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't

Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol), published in United States. (Language: eng)

Reference: 2009-Jul; vol 297 (issue 1) : pp H37-46

Dates: Created 2009/06/30; Completed 2009/08/12;

PMID: 19429816, status: MEDLINE (last retrieved date: 8/21/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals
Antibiotics, Antineoplastic - antagonists & inhibitors; toxicity
Biological Markers
Creatine Kinase - metabolism
Cytochrome P-450 Enzyme System - biosynthesis; genetics; physiology
Doxorubicin - antagonists & inhibitors; toxicity
Echocardiography
Female
Gene Expression - genetics

Heart Diseases - chemically induced; physiopathology
Heart Function Tests
Humans
In Situ Nick-End Labeling
L-Lactate Dehydrogenase - metabolism
Male
Mice
Mice, Transgenic
Mitochondria, Heart - drug effects

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Antibiotics, Antineoplastic (0) ; Biological Markers (0) ; Doxorubicin (23214-92-8) ; Cytochrome P-450 Enzyme System (9035-51-2) ; L-Lactate Dehydrogenase (EC 1.1.1.27) ; arachidonate epoxygenase (EC 1.14.14.1) ; Creatine Kinase (EC 2.7.3.2)

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