D-serine-induced nephrotoxicity: possible interaction with tyrosine metabolism.
D-serine selectively damages renal proximal tubule cells in rats by a mechanism that is not fully understood. Recent proteomic analysis identified that D-serine elevated plasma fumarylacetoacetate hydrolase (FAH). FAH is involved in tyrosine catabolism; hence, this pathway may be involved in mediating the toxicity. This work examines whether 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC), a potent inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) located upstream of FAH, modulates D-serine-induced nephrotoxicity. Rats were pretreated with NTBC (0.5 mg/kg p.o.) or corn oil and then 30 min later given either D-serine (250 mg/kg i.p.) or water. Urine was collected every 12 h until termination (48 h) and analysed by 1H NMR spectroscopy and principal component analysis (PCA). Markers of proximal tubule injury were evident in urine following treatment with D-serine and NTBC + D-serine. PCA could not distinguish between these urine samples suggesting that NTBC does not effect the development of nephrotoxicity. Clinical chemistry analysis of urine and terminal plasma samples and histopathological examination of the kidneys confirmed this. NTBC alone caused a marked increase in the excretion of 4-hydroxyphenylpyruvate (HPPA) and 4-hydroxyphenyllactate (HPLA); however, HPPA and HPLA excretion was minimal following NTBC + D-serine. Instead marked tyrosinuria was observed suggesting that D-serine-induced renal damage markedly affects the handling of increased levels of HPPA and HPLA resulting from the inhibition of HPPD.
Williams
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Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK. becky.williams@astrazeneca.com
Lock
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D000818:Animals; D003512:Cyclohexanones / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006867:Hydrolases / Q000627:therapeutic use*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009579:Nitrobenzoates / Q000627:therapeutic use*; D010667:Phenylpyruvic Acids / Q000378:metabolism / Q000652:urine; D051381:Rats; D012694:Serine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D014443:Tyrosine / Q000378:metabolism* / Q000652:urine
D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D010667:Phenylpyruvic Acids; C010590:4-hydroxyphenylpyruvic acid; D014443:Tyrosine; D012694:Serine; D006867:Hydrolases; C020156:fumarylacetoacetase; C077073:nitisinone