Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity

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.

Loss of Multidrug Resistance–Associated Protein 1 Potentiates Chronic Doxorubicin-Induced Cardiac Dysfunction in Mice

“…All experiments complied with the requirements of the University of Kentucky Institutional Animal Care and Use Committee. The animal treatment protocols were based on studies demonstrating decreased cardiac function after chronic treatment with DOX (Zhang et al, 2009). All experiments used male mice aged 10-12 weeks weighing 25-35 g. Mice were administered intraperitoneal DOX (Pfizer, NY) at a dose of 3 mg/kg body weight (protocol A) or 2 mg/kg body weight (protocol B), or an equivalent volume of saline, twice a week for 3 or 5 weeks, resulting in a cumulative DOX dose of 18 mg/kg (protocol A) or 20 mg/kg (protocol B) (Fig.…”

“…The authors thank Dr. John Seubert (University of Alberta, Edmonton, AB, Canada) for numerous helpful discussions regarding the chronic DOX treatment model (Zhang et al, 2009). Conducted experiments: Zhang.…”

Cytochrome P450 enzymes and the heart

“…Recently, Zhang et al reported mice with cardiomyocyte specific overexpression of CYP2J2 had reduced doxorubicin-induced cardiotoxicity. The reduced toxicity was partially attributed to increased metabolism of doxorubicin by microsomes prepared from CYP2J2 hearts (17). Exposure to drugs, such as cocaine, can induce the CYP expression in the heart (60).…”

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

“…These EETs have many biological functions including, but not limited to, angiogenesis, regulation of vasodilation, inhibition of cytokine-induced endothelial cell adhesion-molecule expression, inhibition of vascular smooth muscle cell migration, protection of endothelial cells against hypoxia-reoxygenation injury, upregulation of endothelial nitric oxide biosynthesis, and protection of doxorubicin-induced cardiotoxicity (Larsen et al, 2007;Spector and Norris, 2007;Yang et al, 2009;Zhang et al, 2009;Campbell and Fleming, 2010;Pfister et al, 2010). All these events are involved in cardiac electrophysiology and protect the heart from ischemic-reperfusion injury (Spiecker and Liao, 2006).…”