Oral Glutamine Protects against Acute Doxorubicin-Induced Cardiotoxicity of Tumor-Bearing Rats

Abstract

Doxorubicin (DOX), a widely used anticancer drug, has a dose-dependent cardiotoxicity, attributed mainly to free radical formation. The cardiomyocyte oxidative stress occurs rapidly after DOX treatment, resulting in harmful modifications to proteins, lipids, and DNA. Previous data showed that oral l-glutamine (Gln) prevented cardiac lipid peroxidation and maintained normal cardiac glutathione (GSH) levels in DOX-treated rats. Our aim in this study was to examine the effect of Gln on DOX-induced cardiac oxidative stress in a tumor-bearing host. Female Fisher344 rats with implanted MatBIII mammary tumors were randomized into 2 groups: a Gln group that received l-Gln (1 g.kg(-1).d(-1)) (n = 10) via a Gln-enriched diet and/or gavage with 50% Gln suspension during the whole experiment and a control group that was fed the same diet formulation without Gln and/or were gavaged with water. All rats received a single injection of 12 mg/kg DOX and were killed 3 d later. GSH levels of hearts, livers, tumors, and blood, as well as cardiac histological alterations, lipid peroxidation, peroxinitrite levels, and caspase-3 activation were determined. Cardiac physiologic alterations were assessed by ultrasound imaging before and 3 d after DOX administration. The Gln supplementation resulted in lower cardiac lipid peroxidation and peroxintrite levels and elevated cardiac catalase enzyme activity and GSH compared with the controls, without affecting those of the tumors. DOX-induced alterations of the echocardiographic parameters were significantly reduced in the Gln-supplemented rats. These data indicate that Gln is able to reduce the oxidative damage of cardiomyocytes that occurs soon after DOX administration and thus protects the heart of a tumor-bearing host from DOX-induced cardiomyopathy.

Treatment of Mice with Naringin Alleviates the Doxorubicin-Induced Oxidative Stress in the Liver of Swiss Albino Mice

“…40,41,43 Similarly L-glutamine has been also reported to protect against the DPX-induced lipid peroxidation. 61 The exact mechanism by which naringin attenuated the DOXinduced oxidative stress is not clearly understood. The naringin may have employed multiple putative mechanisms to alleviate the DOXinduced oxidative stress.…”

“…62 Glutamine an amino acid has been reported to protect against the DOX-induced depletion in GSH in rats. 61 The reduction in doxorubicin-induced oxidative stress may be due to its ability to neutralize doxorubicin-induced free radicals and ROS or its ability to participate through other enzymatic reactions. 66 Glutathione-s-transferases or GSTs are a multi gene family of enzymes, which are found in almost all organisms.…”

“…Similarly DOX has been found to reduce GSH level in mice and rat liver and heart earlier. 32,[61][62][63] Naringin treatment has been found to elevate the GSH concentration in the heart and liver of doxorubicin treated mice and rats. 32,[63][64][65] Similarly, extract of Agele marmalos has been reported to elevate myocardial glutathione in mice.…”

“…DOX treatment has been earlier reported to increase the lipid peroxidation in rat and mice. 32,[61][62][63][64][65]72 Naringin treatment has been found to protect mouse and rat liver and heart against the DOX-induced lipid peroxidation. 32,[63][64][65] Naringin has also been reported to protect against iron and bleomycin-induced lipid peroxidation in earlier studies.…”

Ameliorative effect of supplementation with l-glutamine on oxidative stress, DNA damage, cell viability and hepatotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat hepatocyte cultures

“…The increased production of reactive oxygen species, lipid peroxidation, and DNA and membrane damage are always associated with TCDD exposure (Shertzer et al 1998). Gln acted as a potent oxygen radical scavenger shown to be beneficial to carcinoma prognosis (Todorova et al 2010). Recently, Gln has been reported to possess anticancer properties (Halder et al 2010).…”