Dietary flaxseed oil supplementation ameliorates the effect of cisplatin on brush border membrane enzymes and antioxidant system in rat intestine

Cisplatin (CP, cis diamminedichloroplatinum II) is a drug widely used against different types of solid tumors. Patients receiving CP, however, experience very profound and long lasting gastrointestinal symptoms. Recently, n3 polyunsaturated fatty acid enriched flaxseed/flaxseed oil (FXO) has shown numerous health benefits. The present study was undertaken to investigate whether FXO can prevent CP induced adverse biochemical changes in the small intestine of rats. A single intraperitoneal dose of CP (6 mg/kg body weight) was administered to male Wistar rats fed with control diet (CP group) and FXO diet (CPFXO group). Administration of CP led to a significant decline in the specific activities of brush border membrane enzymes both in the mucosal homogenates and in the isolated membrane vesicles. Lipid peroxidation and total sulfhydryl groups were altered upon CP treatment, indicating the generation of oxidative stress. The activities of SOD, catalase and glutathione peroxidase also decreased in CP-treated rats. In contrast, dietary supplementation of FXO prior to and following CP treatment significantly attenuated the CP induced changes in all these parameters. FXO feeding markedly enhanced resistance to CP elicited adverse gastrointestinal effects. The results suggest that FXO owing to its intrinsic biochemical and antioxidant properties is an effective agent in reducing the adverse effects of CP on intestine. (Authors abstract)
Cisplatin (CP, cisdiamminedichloroplatinum II) has been established as a potent chemotherapeutic agent administered to treat a variety of cancers. However, its use in combating cancer is limited by the development of nephrotoxicity and gastrointestinal toxicity.  Increased production of reactive oxygen species (ROS) and free radicals has been implicated in mediating CP-induced toxicity. These radicals can cause extensive tissue damage by reacting with macromolecules like membrane lipids, proteins and nucleic acids. Inhibitors of ROS accumulation can block CP induced toxicity.  Flaxseed oil (FXO) has been shown to increase the life span of irradiated mice, suggesting its prophylactic potential against radiation-induced degenerative changes in liver. The objective of the study was to determine if FXO would prevent CP induced adverse effects on intestine due to its antioxidant properties. The effect of CP alone and CP plus FXO diet on the functional integrity of the mucosal membrane, as determined from the activity of BBM enzymes and antioxidant status in rats was tested.  The brush border membrane (BBM) lining the enterocytes contains a number of hydrolytic enzymes and is the major site of digestion and transport of nutrients.The integrity of the membrane was assessed by the status of its biomarker enzymes ALP, GGTase, LAP and sucrase. A decrease in the activities of BBM enzymes was seen upon administration of CP. The decrease in enzyme activities could be due to the direct modification and consequent inactivation of enzymes by CP generated free radicals and ROS. There could also have been leakage or loss of these enzymes into the lumen of the intestine following ROS induced damage to the epithelial cells, especially the membrane. Dietary FXO supplementation prior to and after CP treatment (CPFXO group) reduced the CP induced decline in the activities of BBM enzymes. Since CP is well known to induce oxidative stress, the protective effect of FXO on CP induced decline in BBM enzyme activities could have been due to the antioxidant properties associated with its biologically active components namely n3 PUFA. In contrast to CP (CP group), FXO consumption (FXO group) enhanced the activities of BBM enzymes indicating an overall improvement in intestinal BBM integrity. The feeding of FXO diet to CP treated rats prevented CP induced suppression of antioxidant enzyme activities. Taken together, the results suggest that ROS (oxygen free radicals) could contribute to the development of gastrointestinal tract toxicity during CP chemotherapy and treatment with FXO considerably ameliorates the CP induced biochemical changes in intestine. The results demonstrate that FXO empowers the antioxidant defense system by reducing oxidative stress and increasing the activities of the major antioxidant enzymes SOD, CAT and GPx. (Editors summary)