Silibinin ameliorates arsenic induced nephrotoxicity by abrogation of oxidative stress, inflammation and apoptosis in rats.
Arsenic (As) is an environmental and industrial pollutant that affects various organs in human and experimental animals. Silibinin is a naturally occurring plant bioflavonoid found in the milk thistle of Silybum marianum, which has been reported to have a wide range of pharmacological properties. A body of evidence has accumulated implicating the free radical generation with subsequent oxidative stress in the biochemical and molecular mechanisms of As toxicity. Since kidney is the critical target organ of chronic As toxicity, we carried out this study to investigate the effects of silibinin on As-induced toxicity in the kidney of rats. In experimental rats, oral administration of sodium arsenite [NaAsO(2), 5 mg/(kg day)] for 4 weeks significantly induced renal damage which was evident from the increased levels of serum urea, uric acid, creatinine with a significant (p < 0.05) decrease in creatinine clearance. As also significantly decreased the levels of urea, uric acid and creatinine in urine. A markedly increased levels of lipid peroxidation markers (thiobarbituric acid reactive substances and lipid hydroperoxides) and protein carbonyl contents with significant (p < 0.05) decrease in non-enzymatic antioxidants (total sulfhydryl groups, reduced glutathione, vitamin C and vitamin E) and enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferase), Glutathione metabolizing enzymes (glutathione reductase and glutathione-6-phosphate dehydrogenase) and membrane bound ATPases were also observed in As treated rats. Co-administration of silibinin (75 mg/kg day) along with As resulted in a reversal of As-induced biochemical changes in kidney accompanied by a significant decrease in lipid peroxidation and an increase in the level of renal antioxidant defense system. The histopathological and immunohistochemical studies in the kidney of rats also shows that silibinin (75 mg/kg day) markedly reduced the toxicity of As and preserved the normal histological architecture of the renal tissue, inhibited the caspase-3 mediated tubular cell apoptosis and decreased the NADPH oxidase, iNOS and NF-κB over expression by As and upregulated the Nrf2 expression in the renal tissue. The present study suggests that the nephroprotective potential of silibinin in As toxicity might be due to its antioxidant and metal chelating properties, which could be useful for achieving optimum effects in As-induced renal damage.
Department of Zoology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India. smprabu73@gmail.com
S Milton
SM
Prabu
M
M
Muthumani
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000633:toxicity* / Q000652:urine; D015415:Biomarkers / Q000097:blood / Q000652:urine; D053148:Caspase 3 / Q000378:metabolism; D004327:Drinking Behavior / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000188:drug therapy* / Q000473:pathology* / Q000652:urine; D008566:Membranes / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D000077385:Silybin; D012838:Silymarin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
D000975:Antioxidants; D015415:Biomarkers; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495637:Nfe2l2 protein, rat; D012838:Silymarin; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000077385:Silybin; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; D053148:Caspase 3; D000251:Adenosine Triphosphatases; D001151:Arsenic