d-Serine-induced nephrotoxicity: a HPLC–TOF/MS-based metabonomics approach

• Published in: Toxicology (Amsterdam) 2005-02, Vol.207 (2), p.179-190
• Main Authors: Williams, R.E., Major, H., Lock, E.A., Lenz, E.M., Wilson, I.D.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Chromatography, High Pressure Liquid; d-Serine; Glycosuria - chemically induced; HPLC–MS; Kidney; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney Tubular Necrosis, Acute - chemically induced; Kidney Tubular Necrosis, Acute - metabolism; Kidney Tubular Necrosis, Acute - pathology; Male; Medical sciences; Metabonomics; Proteinuria - chemically induced; Proximal tubule; Rats; Rats, Inbred Strains; Renal Aminoacidurias - chemically induced; Serine - metabolism; Serine - toxicity; Serine - urine; Spectrometry, Mass, Electrospray Ionization; Toxicology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2004.08.023

HPLC–MS-based metabonomic analysis was used to investigate urinary metabolic perturbations associated with d-serine-induced nephrotoxicity. d-Serine causes selective necrosis of the proximal straight tubules in the rat kidney accompanied by aminoaciduria, proteinuria and glucosuria. Alderely Park (Wistar-derived) rats were dosed with either d-serine (250 mg/kg ip) or vehicle (deionised water) and urine was collected at 0–12, 12–24, 24–36 and 36–48 h post-dosing. Samples were analysed using a Waters Alliance ® HT 2795 HPLC system coupled to a Waters Micromass Q-ToF-micro™ equipped with an electrospray source operating in either positive or negative ion mode. Changes to the urinary profile were detected at all time points compared to control. In negative ion mode, increases were observed in serine ( m/ z = 103.0077), m/ z = 104.0376 (proposed to be hydroxypyruvate) and glycerate ( m/ z = 105.0215), the latter being metabolites of d-serine. Furthermore, an increase in tryptophan, phenylalanine and lactate and decreases in methylsuccinic acid and sebacic acid were observed. Positive ion analysis revealed a decrease in xanthurenic acid, which has previously been assigned and reported using HPLC–MS following exposure to mercuric chloride and cyclosporine A. A general aminoaciduria, including proline, methionine, leucine, tyrosine and valine was also observed as well as an increase in acetyl carnitine. Investigation of additional metabolites altered as a result of exposure to d-serine is on-going. Thus, HPLC–MS-based metabonomic analysis has provided information concerning the mechanism of d-serine-induced renal injury.