title: Inhibition of cystathionine gamma-lyase and the biosynthesis of endogenous hydrogen sulphide ameliorates gentamicin-induced nephrotoxicity.
abstract: 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.
authors.affiliation: Department of Pharmacology & Physiology, School of Veterinary & Biomed Sciences, James Cook University, 1 Solander Drive Douglas, Qld 4811, Australia.
authors.forename: Van P
authors.initials: VP
authors.lastname: Dam
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Scott
authors.forename: Anthony
authors.initials: A
authors.lastname: Ross
authors.forename: Robert T
authors.initials: RT
authors.lastname: Kinobe
mesh_terms: D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors*; D005260:Female; D005839:Gentamicins / Q000633:toxicity*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D015227:Lipid Peroxidation / Q000187:drug effects; D009336:Necrosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000494:pharmacology
chemical_list: D000480:Alkynes; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D013440:Sulfides; C009055:propargylglycine; D003542:Cystathionine gamma-Lyase; C025451:sodium bisulfide; D005998:Glycine; D006862:Hydrogen Sulfide