Chronic Doxorubicin Cardiotoxicity Modulates Cardiac Cytochrome P450-Mediated Arachidonic Acid Metabolism in Rats

Alsaad, Abdulaziz M.S.; Zordoky, Beshay N.; El-Sherbeni, Ahmed A.; El‐Kadi, Ayman O.S.

doi:10.1124/dmd.112.046631

Cited by 45 publications

(23 citation statements)

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“…Therefore, the underlying mechanisms of sexual dimorphism in DOX-induced toxicity are still poorly understood. A growing body of evidence suggests an important role of CYP enzymes in the pathogenesis of DOX-induced cardiotoxicity [19, 47, 48]. CYP enzymes play important roles in metabolizing sex steroids and other endogenous compounds, such as arachidonic acid that have significant biological effects on the cardiovascular system [20].…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl/6 mice

et al. 2017

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BackgroundThere is inconclusive evidence about the role of sex as a risk factor for doxorubicin (DOX)-induced cardiotoxicity. Recent experimental studies have shown that adult female rats are protected against DOX-induced cardiotoxicity. However, the mechanisms of this sexual dimorphism are not fully elucidated. We have previously demonstrated that DOX alters the expression of several cytochrome P450 (CYP) enzymes in the hearts of male rats. Nevertheless, the sex-dependent effect of DOX on the expression of CYP enzymes is still not known. Therefore, in the present study, we determined the effect of acute DOX exposure on the expression of CYP genes in the hearts of both male and female C57Bl/6 mice.MethodsAcute DOX cardiotoxicity was induced by a single intraperitoneal injection of 20 mg/kg DOX in male and female adult C57Bl/6 mice. Cardiac function was assessed 5 days after DOX exposure by trans-thoracic echocardiography. Mice were euthanized 1 day or 6 days after DOX or saline injection. Thereafter, the hearts were harvested and weighed. Heart sections were evaluated for pathological lesions. Total RNA was extracted and expression of natriuretic peptides, inflammatory and apoptotic markers, and CYP genes was measured by real-time PCR.ResultsAdult female C57Bl/6 mice were protected from acute DOX-induced cardiotoxicity as they show milder pathological lesions, less inflammation, and faster recovery from DOX-induced apoptosis and DOX-mediated inhibition of beta-type natriuretic peptide. Acute DOX exposure altered the gene expression of multiple CYP genes in a sex-dependent manner. In 24 h, DOX exposure caused male-specific induction of Cyp1b1 and female-specific induction of Cyp2c29 and Cyp2e1.ConclusionsAcute DOX exposure causes sex-dependent alteration of cardiac CYP gene expression. Since cardiac CYP enzymes metabolize several endogenous compounds to biologically active metabolites, sex-dependent alteration of CYP genes may play a role in the sexual dimorphism of acute DOX-induced cardiotoxicity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0124-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl/6 mice

et al. 2017

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“…There are conflicting reports of sEH expression in mouse pressure-induced models of hypertrophy, where no change or a reduction in sEH protein and mRNA expression is detected in heart tissue (Xu et al, 2006; Morgan et al, 2012). Chronic treatment with doxorubicin increases hypertrophic, inflammatory and apoptotic markers as well as sEH mRNA expression in the rat heart (Alsaad et al, 2012). Finally, Arsenic-III treatment increases mRNA expression of hypertrophic markers as well as protein and mRNA levels of sEH in the mouse heart (Anwar-Mohamed et al, 2012).…”

Section: Mammalian Gene Expressionmentioning

confidence: 99%

Soluble epoxide hydrolase: Gene structure, expression and deletion

Harris

Hammock

2013

Gene

191

184

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Mammalian soluble epoxide hydrolase (sEH) converts epoxides to their corresponding diols through the addition of a water molecule. sEH readily hydrolyzes lipid signaling molecules, including the epoxyeicosatrienoic acids (EETs), epoxidized lipids produced from arachidonic acid by the action of cytochrome p450s. Through its metabolism of the EETs and other lipid mediators, sEH contributes to the regulation of vascular tone, nociception, angiogenesis and the inflammatory response. Because of its central physiological role in disease states such as cardiac hypertrophy, diabetes, hypertension, and pain sEH is being investigated as a therapeutic target. This review begins with a brief introduction to sEH protein structure and function. sEH evolution and gene structure are then discussed before human small nucleotide polymorphisms and mammalian gene expression are described in the context of several disease models. The review ends with an overview of studies that have employed the sEH knockout mouse model.

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“…61–63 Herein, we present a different mechanism (Figure 8) based on our data by which DOX may alter AA metabolism in humans, namely, through direct inhibition of CYP2J2 and the binding of 7-de-aDOX that concurrently changes the EET regioselectivity. DOX generates ROS that initiates an assault on cardiac cells.…”

Section: Discussionmentioning

confidence: 99%

Arachidonic Acid Metabolism by Human Cardiovascular CYP2J2 Is Modulated by Doxorubicin

et al. 2017

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Doxorubicin (DOX) is a chemotherapeutic that is used in the treatment of a wide variety of cancers. However, it causes cardiotoxicity partly due to the formation of reactive oxygen species (ROS). CYP2J2 is a human cytochrome P450 that is highly expressed in cardiomyocytes. It converts arachidonic acid (AA) into four different regioisomers of epoxyeicosatrienoic acids (EETs). Using kinetic analyses we show that AA metabolism by CYP2J2 is modulated by DOX. We show that cytochrome P450 reductase (CPR), the redox partner of CYP2J2, metabolizes DOX to 7-deoxydoxorubicin aglycone (7-de-aDOX). This metabolite then binds to CYP2J2, and inhibits and alters the preferred site of metabolism of AA leading to change in the ratio of the EET regioisomers. Furthermore, molecular dynamics (MD) simulations indicate that 7-de-aDOX and AA can concurrently bind to the CYP2J2 active site to produce these changes in the site of AA metabolism. To see if these observations are unique to DOX/7-de-aDOX, we use non-cardiotoxic DOX analogues, zorubicin (ZRN) and 5-iminodaunorubicin (IDN). ZRN and 5-IDN inhibit CYP2J2-mediated AA metabolism, but does not change the ratio of EET regioisomers. Taken together, we demonstrate that DOX and 7-de-aDOX inhibit CYP2J2-mediated AA metabolism and 7-de-aDOX binds close to the active site to alter the ratio of cardioprotective EETs. These mechanistic studies of CYP2J2 can aid in the design of new alternative DOX derivatives.

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Chronic Doxorubicin Cardiotoxicity Modulates Cardiac Cytochrome P450-Mediated Arachidonic Acid Metabolism in Rats

Cited by 45 publications

References 45 publications

Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl/6 mice

Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl/6 mice

Soluble epoxide hydrolase: Gene structure, expression and deletion

Arachidonic Acid Metabolism by Human Cardiovascular CYP2J2 Is Modulated by Doxorubicin

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