Acute Doxorubicin Toxicity Differentially Alters Cytochrome P450 Expression and Arachidonic Acid Metabolism in Rat Kidney and Liver

Zordoky, Beshay N.; Anwar-Mohamed, Anwar; Aboutabl, Mona E.; El‐Kadi, Ayman O.S.

doi:10.1124/dmd.111.039123

Cited by 74 publications

(57 citation statements)

References 36 publications

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“…and IL-6 [10,32,33], TNF-α [9,10,32,33] and cyclooxygenase-2 (COX-2) [34]. In agreement with these studies [9,10,32,33,34], DOX in our experimental model markedly elicited inflammatory response, as evidenced by an increase in the production of IL-1β, IL-6 and TNF-α.…”

Section: Discussionsupporting

confidence: 76%

Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NFκB Pathway in H9c2 Cardiac Cells

Guo

Chen

et al. 2013

Cell Physiol Biochem

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Background/Aim:We have demonstrated that exogenous hydrogen sulfide (H₂S) protects H9c2 cardiac cells against the doxorubicin (DOX)-induced injuries by inhibiting p38 mitogen-activated protein kinase (MAPK) pathway and that the p38 MAPK/nuclear factor-κB (NF-κB) pathway is involved in the DOX-induced inflammatory response and cytotoxicity. The present study attempts to test the hypothesis that exogenous H₂S might protect cardiomyocytes against the DOX-induced inflammation and cytotoxicity through inhibiting p38 MAPK/NF-κB pathway. Methods: H9c2 cardiac cells were exposed to 5µM DOX for 24 h to establish a model of DOX cardiotoxicity. The cells were pretreated with NaHS( a donor of H₂S) or other drugs before exposure to DOX. Cell viability was analyzed by cell counter kit 8 ( CCK-8), The expression of NF-κB p65 and inducible nitric oxide synthase (iNOS) was detected by Western blot assay. The levels of interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-a (TNF-a) were tested by enzyme-linked immunosorbent assay (ELISA). Results: Our findings demonstrated that pretreatment of H9c2 cardiac cells with NaHS for 30 min before exposure to DOX markedly ameliorated the DOX-induced phosphorylation and nuclear translocation of NF-κB p65 subunit. Importantly, the pretreatment with NaHS significantly attenuated the p38 MAPK/NF-κB pathway-mediated inflammatory responses induced by DOX, as evidenced by decreases in the levels of IL-1ß, IL-6 and TNF-a. In addition, application of NaHS or IL-1ß receptor antagonist (IL-1Ra) or PDTC (an inhibitor of NF-κB) attenuated the DOX-induced expression of iNOS and production of nitric oxide (NO), respectively. Furthermore, IL-1Ra also dramatically reduced the DOX-induced cytotoxicity and phosphorylation of NF-κB p65. The pretreatment of H9c2 cells with N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS) prior to exposure to DOX depressed the phosphorylation of NF-κB p65 induced by DOX. Conclusion: The present study has demonstrated the new mechanistic evidence that exogenous H₂S attenuates the DOX-induced inflammation and cytotoxicity by inhibiting p38 MAPK/NF-κB pathway in H9c2 cardiac cells. We also provide novel data that the interaction between NF-κB pathway and IL-1ß is important in the induction of DOX-induced inflammation and cytotoxicity in H9c2 cardiac cells.

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Section: Discussionsupporting

confidence: 76%

Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NFκB Pathway in H9c2 Cardiac Cells

Guo

Chen

et al. 2013

Cell Physiol Biochem

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“…‫,ء‬ p Ͻ 0.05 compared with the control. kidney, which is in agreement with the acute DOX model (Zordoky et al, 2011). This induction could be attributed to the activation of the aryl hydrocarbon receptor and to the DOX-induced inflammation.…”

Section: Effect Of Doxorubicin On Cytochrome P450 Expressionsupporting

confidence: 77%

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

et al. 2012

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ABSTRACT:Doxorubicin [(DOX) Adriamycin] is an effective anticancer agent whose major limiting side effect is cardiotoxicity. This cardiotoxicity is predicted only by the cumulative dose of DOX where the clinical situation involves chronic drug administration. Therefore, we investigate the effect of chronic DOX cardiotoxicity on expression of the cardiac cytochrome P450 (P450) enzymes and arachidonic acid (AA) metabolism in male Sprague-Dawley (SD) rats. The chronic toxicity was induced by multiple intraperitoneal injections for a cumulative dose of 15 mg/kg divided into six injections within 2 weeks. After 14 days of the last injection, the heart, liver, and kidney were harvested, and the expression of different genes was determined by real-time polymerase chain reaction. In addition, microsomal protein from the heart was prepared and incubated with AA. Thereafter, different AA metabolites were analyzed by liquid chromatography-electrospray ionization-mass spectrometry. The chronic DOX cardiotoxicity significantly induced gene expression of hypertrophic markers, apoptotic markers, CYP2E1, CYP4A3, CYP4F1, CYP4F5, and soluble epoxide hydrolase (sEH) enzyme, which was accompanied by an increase in the activity of P450 -hydroxylases and sEH. In addition, both the sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid, and the -hydroxylase inhibitor, N-hydroxy-N-(4-butyl-2-methylphenyl)-formamidine (HET0016), significantly prevented the DOX-mediated induction of the hypertrophic markers in the cardiacderived H9c2 cells, which further confirms the role of these enzymes in DOX cardiotoxicity. Furthermore, gene expression of P450 and sEH was altered in an organ-specific manner. As a result, the chronic DOX administration leads to an imbalance between P450-mediated cardiotoxic and cardioprotective pathways. Therefore, P450 -hydroxylases and sEH might be considered as novel targets to prevent and/or treat DOX cardiotoxicity.

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“…More patients require treatment for cancer and experience severe side-effects following treatment with various anti-cancer drugs (30,31). DOX is used clinically as an anti-cancer drug, however its therapeutic application is been limited due to the serious adverse reactions experienced by patients, which affect the heart, liver and other organs (13,14). In the current study, a high dose of DOX was used to induce cardiotoxicity and hepatotoxicity in mice.…”

Section: Discussionmentioning

confidence: 99%

“…However, even at clinically relevant doses, the therapeutic application of DOX is limited by systemic toxicity, including cardiotoxicity, hepatotoxicity and nephrotoxicity (13,14). DOX promotes reactive oxygen species (ROS), which mediates these organ toxicities (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Magnesium isoglycyrrhizinate ameliorates doxorubicin‑induced acute cardiac and hepatic toxicity via anti‑oxidant and anti‑apoptotic mechanisms in mice

Zhang

Song

et al. 2017

Exp Ther Med

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Abstract. The present study investigated the effects and potential mechanisms of action of magnesium isoglycyrrhizinate (MgIG) in doxorubicin (DOX)-treated mice. Histopathological analysis and western blot analysis were conducted in the liver and heart tissues and biochemical analysis of the serum was performed. The results revealed that MgIG (10, 20 and 40 mg/kg/day) could protect the structure and functions of the liver and heart by inhibiting the activities of the myocardial enzymes creatine kinase (CK), CK-MB and lactate dehydrogenase and the hepatic-specific enzymes aspirate aminotransferase and alanine aminotransferase, increasing the activities of the antioxidants superoxide dismutase and glutathione peroxidase, and inhibiting cellular apoptosis induced by DOX (30 mg/kg). These results demonstrate that inhibiting lipid peroxidation and reducing myocardial and hepatocyte apoptosis may be one of the mechanisms by which MgIG exhibits hepatoprotective and cardioprotective effects in DOX-treated mice.

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Acute Doxorubicin Toxicity Differentially Alters Cytochrome P450 Expression and Arachidonic Acid Metabolism in Rat Kidney and Liver

Cited by 74 publications

References 36 publications

Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NFκB Pathway in H9c2 Cardiac Cells

Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NFκB Pathway in H9c2 Cardiac Cells

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

Magnesium isoglycyrrhizinate ameliorates doxorubicin‑induced acute cardiac and hepatic toxicity via anti‑oxidant and anti‑apoptotic mechanisms in mice

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Acute Doxorubicin Toxicity Differentially Alters Cytochrome P450 Expression and Arachidonic Acid Metabolism in Rat Kidney and Liver

Cited by 74 publications

References 36 publications

Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NF&#954;B Pathway in H9c2 Cardiac Cells

Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NF&#954;B Pathway in H9c2 Cardiac Cells

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

Magnesium isoglycyrrhizinate ameliorates doxorubicin‑induced acute cardiac and hepatic toxicity via anti‑oxidant and anti‑apoptotic mechanisms in mice

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Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NFκB Pathway in H9c2 Cardiac Cells

Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NFκB Pathway in H9c2 Cardiac Cells