1H NMR pattern recognition and 31P NMR studies with d-Serine in rat urine and kidney, time- and dose-related metabolic effects.
Proton NMR spectroscopy of urine has previously been used to gain insight into the site and mechanism of toxic injury to the kidney. d-Serine injures the rat kidney, causing selective necrosis of the proximal straight tubules. Damage is accompanied by proteinuria, glucosuria, and amino aciduria, the latter preceding the onset of necrosis. This study has employed (1)H NMR spectroscopy of urine and (1)H NMR and (31)P NMR spectroscopy of kidney extracts to examine the nephrotoxic action of d-serine. Urine was collected 0-8 h (all doses) and 8-24, 24-48, 48-72, 72-96, and 96-120 h (500 mg/kg only) postdosing from Alderley Park rats given d-serine (62.5, 125, 250, and 500 mg/kg ip). (1)H NMR spectra were monitored for markers of tubular damage. Additionally, ATP and ADP were quantitated in kidney perchloric acid extracts, prepared after 0.5, 1, 2, 4, and 8 h (500 mg/kg) to assess energy status; serine was also measured in these samples. At 500 mg/kg, glucosuria, amino aciduria, and reduced citrate, alpha-ketoglutarate, and succinate were observed in urine at 0-8 h. Furthermore, serine and pyruvate levels were elevated at this time. After 8-24 h, similar changes were observed; however, they were more severe reflecting the development of the lesion prior to recovery. These perturbations were dose-related, in particular, for serine and pyruvate, with no alterations seen at 62.5 mg/kg. Kidney serine concentration rapidly increased, where it was maximal after 30 min and cleared by 8 h. A decline in ATP, to approximately 60-70% of control, was observed within the kidney at 2-4 h postdosing, when necrosis first becomes evident suggesting that mitochondrial function might be impaired in the early stages of d-serine-induced nephrotoxicity. The use of NMR spectroscopy has given a comprehensive overview of the effects of d-serine in vivo. Information on the excretion of serine and its effect on renal energy metabolism provides insight into the possible mechanism of renal tubule injury.
Williams
Rebecca E
RE
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom. becky.williams@astrazeneca.com
Jacobsen
Matthew
M
Lock
Edward A
EA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D019344:Lactic Acid / Q000652:urine; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D009336:Necrosis; D010759:Phosphorus Isotopes; D019289:Pyruvic Acid / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine*; D013997:Time Factors; D014556:Urine / Q000737:chemistry
D010759:Phosphorus Isotopes; D019344:Lactic Acid; D012694:Serine; D019289:Pyruvic Acid