Oral Glutamine Attenuates Cyclophosphamide-Induced Oxidative Stress in the Bladder but Does Not Prevent Hemorrhagic Cystitis in Rats

Abstract

Cyclophosphamide (CP) is widely used in the treatment of cancer and non-malignant disease states such as rheumatoid arthritis. Hemorrhagic cystitis is a major dose-limiting side effect of CP. The incidence of this side effect is related to the dosage and can be as high as 75%. Elimination of the side effects of CP can lead to better tolerance of the drug, and a more efficient therapy can be achieved for patients in need of CP treatment. Several studies have demonstrated that oxidative stress and neutrophil infiltration play important roles in CP-induced bladder damage. Glutamine is utilized under clinical conditions for preventing chemotherapeutic drug-induced side effects, based on its ability to attenuate oxidative stress. The aim of the study is to verify whether glutamine prevents CPinduced oxidative stress and bladder damage using a rat model. Adult male rats were administered 150 mg/kg body weight of CP intraperitoneally. Glutamine pretreated rats were administered 1 g/kg body weight of glutamine orally 2 h before the administration of CP. Vehicle/ glutamine-treated rats served as controls. All the rats were killed 16 h after the dose of CP/vehicle. The urinary bladders were removed and used for light microscopic and biochemical studies. The markers of oxidative stress including malondialdehyde content, protein carbonyl content, protein thiol, and myeloperoxidase activity, a marker of neutrophil infiltration, were measured in bladder homogenates. CP treatment induced hemorrhagic cystitis in the rats. Pretreatment with glutamine significantly reduced CPinduced lipid peroxidation (p<0.01), protein oxidation (p < 0.01), and increase in myeloperoxidase activity (p<0.05). However, it did not prevent CP-induced bladder damage. The results of the present study show that glutamine pretreatment does not attenuate CP-induced hemorrhagic cystitis, although it prevents CP-induced oxidative stress and neutrophil infiltration significantly. It is therefore necessary to clarify the utility of glutamine as a chemoprotective agent before it is recommended in the market as a nutrient supplement.

Protective effect of N-acetylcysteine on cyclophosphamide-induced cardiotoxicity in rats

“…In agreement with the present study, previous studies suggested that CP generates ROS like superoxide anion, hydroxyl radical and hydrogen peroxide during its oxidative metabolism and depresses the antioxidant defense mechanism in different tissues (Abraham et al, 2011;Senthilkumar et al, 2012).…”

“…CP metabolites, and ROS generated in particular, can cause changes in cell redox balance, which leads to oxidative stress, resulting in cancer and healthy cell damage (Abraham et al, 2011;Jamshidzadeh et al, 2009). Moreover, superoxide radical may react with other radicals including nitric oxide producing peroxynitrite, in the cytosol and mitochondria (Mukhopadhyay et al, 2009).…”

Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation

“…Furthermore, Foxp3 + T cells are often recruited to a tumor before T eff cells are recruited, which prevents the T cell-mediated eradication of the tumor cells (60). Thus, the glutamine-deficient microenvironment of a tumor, potentially caused by the "addiction" of tumor cells to glutamine (61,62) or as an undesirable result of chemotherapy (32)(33)(34), appears to be a critical factor in enforcing a T reg cell phenotype even under conditions in which the CD4 + T cells recruited into the tumor are exposed to conditions that promote their differentiation into effectors. Manipulating the metabolic state of T cells may modulate the balance between effector and suppressor functions, potentially opening new avenues for the development of immunotherapies.…”

“…Specifically, quantitative metabolomics profiling has revealed that the intratumoral concentrations of glucose and glutamine are reduced in patients with hepatocellular carcinomas and stomach and colon tumors (29,30). Furthermore, alkylating chemotherapies decrease the intracellular generation of the antioxidant glutathione because of limited glutamine availability (31)(32)(33)(34).…”

Histological and Biochemical Change in the Liver of Male Albino Rats Treated With Different Doses of Cyclophosphamide

“…17 Previous investigation, which report increased levels of nitric oxide in liver of CP-treated rats; this could be credited to acrolein able to activate both ROS and NOx metabolite production with further production of superoxide anion, hydroxyl radical and hydrogen peroxide during CP oxidative metabolism leading to a depressed antioxidant defense mechanism in different tissues. 18 Increased levels of nitric oxide in liver of CP-treated rats; this could be credited to acrolein able to that decreased glycogen content could be related to the liver damage induced by the released lysosomal hydrolytic enzymes from the hepatocytes following a stimulated lipid peroxidation. 19 The cyclophosphamide induced hepatic histopathological changes.…”