Sodium benzoate attenuates d-serine induced nephrotoxicity in the rat

• Published in: Toxicology (Amsterdam) 2005-02, Vol.207 (1), p.35-48
• Main Authors: Williams, R.E., Lock, E.A.
• Format: Article
• Language: English
• Subjects: 1H NMR spectroscopy; Animals; Biological and medical sciences; Creatinine - blood; d-Amino acid oxidase; D-Amino-Acid Oxidase - antagonists & inhibitors; d-Serine; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Kidney - drug effects; Kidney - enzymology; Kidney - metabolism; Kidney - pathology; Kidney Diseases - chemically induced; Kidney Diseases - drug therapy; Kidney Diseases - enzymology; Kidney Diseases - pathology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - pathology; Male; Medical sciences; Necrosis; Nephrotoxicity; Proximal tubule; Rats; Rats, Inbred Strains; Serine - toxicity; Sodium benzoate; Sodium Benzoate - pharmacokinetics; Sodium Benzoate - therapeutic use; Time Factors; Toxicology; Urea - blood; Urine - chemistry
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2004.08.008

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 ip) 1 h after exposure to SB (125, 250, 500 or 750 mg/kg ip). 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 ip; 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.