Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology
Silymarin increases antioxidant enzymes in alloxan-induced diabetes in rat pancreas
Introduction
It has been proposed that oxidant free radicals play a relevant role in the etiology and pathogenesis of human diabetes mellitus and its sequels like nephropathy, neuropathy and angiopathy (Paolisso et al., 1993). Additionally, to free radicals raised from the electron transport chain, glucose can auto-oxidize, catalyzed by trace amounts of transition metals generating superoxide, and hydroxyl radicals, hydrogen peroxide and reactive ketoaldehydes (Hunt and Dean, 1998). An increase in malondialdehyde concentration was found in serum and erythrocytes of patients with this syndrome (Gutteridge and Halliwell, 1990). This alteration was more pronounced in individuals showing sequential complications (Baynes, 1991). In addition to GSH, there are other defence mechanisms against free radicals like the enzymes superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase (CAT) whose activities contribute to eliminate superoxide (O2) and hydroxyl (OH) radicals.
Alloxan has been widely used to produce experimental diabetes. This compound causes severe necrosis of pancreatic β-cells (Dunn et al., 1943). It has been suggested that alloxan induces the production of H2O2 and of some free radicals such as O2 and OH that produce first damage and later the death of β-cells (Lenzen and Munday, 1991). Given this hypothesis, the above model was considered adequate for the study of a pathology where free radicals might have a central role, such as diabetes mellitus.
Silymarin, a flavonoid extracted from the milk thistle Silybum marianum, has demonstrated protective effects against the oxidative peroxidation in several experimental models and in human hepatic damage (Wellington and Harvis, 2001, Valenzuela and Garrido, 1994). In both cases, silymarin functioned as a free radical scavenger, increasing reduced glutathione (GSH) available which functions as a detoxificant of intermediary oxygen reactive products of lipoperoxidation. Silymarin might function to inhibit enzymatic peroxidation in rats through the lipoxygenase pathway, avoiding leukotriene synthesis (Alarcón de la Lastra et al., 1992).
It was previously demonstrated that silymarin prevented a rise in both plasma glucose and pancreatic lipid peroxidation in alloxan-induced diabetes mellitus in rats (Soto et al., 1998). The aim of this study was to analyze the effect of silymarin on the pancreatic activity of SOD, GSHPx and CAT in alloxan-induced diabetic rats.
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Materials and methods
Silymarin was kindly supplied by Altana Pharma Laboratories (México). All reagents were of analytical grade, obtained from Sigma Chemical Co. (St. Louis, MO, USA) and from local dealers (Merck and J.T. Baker).
The experiments reported in this study were carried out following the guidelines stated in ‘Principles of Laboratory Animal Care’ (NIH publication #85-23, revised 1985) and the Mexican Official Normativity ‘Norma Oficial Mexicana NOM-062-ZOO-1999, Especificaciones técnicas para la
Silymarin effect on serum glucose
Silymarin alone did not induce any change on serum glucose (Fig. 1a). Alloxan treatment produced a significantly sustained increase in serum glucose with respect to control group. The simultaneous treatment with silymarin and alloxan significantly reduced the increase in serum glucose concentration induced by alloxan through a period of 15 days. After this time, serum glucose level increased until it reached the values of alloxan treated group at day 30. Because of this, a group of animals were
Discussion
Previously we demonstrated that silymarin prevented diabetes mellitus induced by alloxan in rats. It was suggested that this effect was owing to an increase in concentrations on plasma and pancreatic glutathione. In this study the main finding was that silymarin prevents a decrease on the pancreatic activities of antioxidant enzymes caused by alloxan when both compounds were administered simultaneously. Interestingly, silymarin restored these enzymatic activities when it was administered for 9
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