Sodium benzoate attenuates D-serine induced nephrotoxicity in the rat.
D-Serine causes selective necrosis to the straight portion of the rat renal proximal tubules. The onset is rapid, occurring within 3-4 h and accompanied by proteinuria, glucosuria and aminoaciduria. The metabolism of D-serine by D-amino acid oxidase (D-AAO) may be involved in the mechanism of toxicity. D-AAO is localized within the peroxisomes of renal tubular epithelial cells, which is also the location of D-serine reabsorption. To address the role of D-AAO in D-serine-induced nephrotoxicity, we have examined the effect of sodium benzoate (SB) on the renal injury. SB has been shown to be a potent, competitive inhibitor of kidney D-AAO in vitro. Male Alderley Park rats were exposed to D-serine (500 mg/kg i.p.) 1 h after exposure to SB (125, 250, 500 or 750 mg/kg i.p.). Urine was collected for 0-6 h, then terminal plasma samples and kidneys were taken at 6.5 h. A second group of animals was given SB (500 mg/kg) followed by D-serine (500 mg/kg i.p.; 1 h later) and urine was collected after 0-6, 6-24 and 24-48 h. Terminal plasma samples and kidneys were taken at 48 h. 1H NMR spectroscopic analysis of urine, combined with principal component analysis, demonstrated that SB was able to prevent D-serine-induced perturbations to the urinary profile in a dose dependent manner. This was confirmed by measurement of plasma creatinine and urinary glucose and protein and histopathological examination of the kidneys. Assessment 48 h after D-serine administration revealed that nephrotoxicity was observed in animals pre-treated with SB (500 mg/kg) although the extent of injury was less pronounced than following D-serine alone. These results demonstrate that whilst prior exposure to SB prevents the initial onset of D-serine-induced nephrotoxicity, renal injury is still apparent at later time points. D-AAO activity in the kidney was decreased by 50% 1 h after dosing with SB suggesting that inhibition of this enzyme may be responsible for the observed protection.
Williams
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Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK.
Lock
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EA
D000818:Animals; D003404:Creatinine / Q000097:blood; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D008297:Male; D009336:Necrosis; D051381:Rats; D011919:Rats, Inbred Strains; D012694:Serine / Q000633:toxicity*; D020160:Sodium Benzoate / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors; D014508:Urea / Q000097:blood; D014556:Urine / Q000737:chemistry
D012694:Serine; D014508:Urea; D003404:Creatinine; D003605:D-Amino-Acid Oxidase; D020160:Sodium Benzoate