Inhibition of cystathionine gamma-lyase and the biosynthesis of endogenous hydrogen sulphide ameliorates gentamicin-induced nephrotoxicity
Dam, Van P., Scott, Jennifer L., Ross, Anthony, and Kinobe, Robert T. (2012) Inhibition of cystathionine gamma-lyase and the biosynthesis of endogenous hydrogen sulphide ameliorates gentamicin-induced nephrotoxicity. European Journal of Pharmacology, 685 (1-3). pp. 165-173.
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Clinical use of gentamicin over prolonged periods is limited because of dose- and time-dependent nephrotoxicity. Primarily, lysosomal phospholipidosis, intracellular oxidative stress and heightened inflammation have been implicated. Hydrogen sulphide is an endogenously produced signal transduction molecule with strong anti-inflammatory, anti-apoptotic and cytoprotective properties. In several models of inflammatory disease however, tissue damage has been associated with increased activity of cystathionine gamma-lyase, biosynthesis of hydrogen sulphide and activation of leukocytes. The aim of this study was to determine effects of inhibiting hydrogen sulphide biosynthesis by DL-propargyl glycine (an irreversible inhibitor of cystathionine gamma-lyase) on inflammation, necrosis and renal function, following treatment with gentamicin in rats. Adult female Sprague–Dawley rats were divided into six groups and treated with; physiological saline, sodium hydrosulphide, DL-propargyl glycine, gentamicin, a combination of gentamicin and sodium hydrosulphide, or gentamicin and DL-propargyl glycine respectively. Gentamicin-induced histopathological changes including inflammatory cell infiltration and tubular necrosis were attenuated by co-administering gentamicin with DL-propargyl glycine (P < 0.05 compared to saline controls and P < 0.05 compared to gentamicin only). Similarly, DL-propargyl glycine caused a significant reduction (P < 0.05) in lipid peroxidation, production of superoxide and the activation of tumour necrosis factor-alpha in gentamicin-treated animals. These data show that protective effects of DL-propargyl glycine might be related at least in part, to the reduced inflammatory responses observed in animals treated with both gentamicin and DL-propargyl glycine. Thus, enzyme systems involved in hydrogen sulphide biosynthesis may offer a viable therapeutic target in alleviating the nephrotoxic effects of gentamicin.
|Item Type:||Article (Refereed Research - C1)|
|Keywords:||gentamicin; nephrotoxicity; cystathionine gamma-lyase; hydrogen sulphide; DL-propargyl glycine; oxidative stress|
|FoR Codes:||11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111501 Basic Pharmacology @ 50%|
11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111502 Clinical Pharmacology and Therapeutics @ 50%
|SEO Codes:||92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920119 Urogenital System and Disorders @ 100%|
|Funders:||Faculty of Medicine, Health and Molecular Science Internal Grant|
|Deposited On:||07 Aug 2012 14:15|
|Last Modified:||18 Oct 2013 01:33|
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