Nephrotoxicity of sevoflurane compound A [fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether] in rats: evidence for glutathione and cysteine conjugate formation and the role of renal cysteine conjugate beta-lyase.
Compound A, which is a breakdown product of the volatile anesthetic sevoflurane, is nephrotoxic in rats, although the mechanism of this toxicity is unknown. In the present investigation, the role of glutathione conjugation, glutathione conjugate processing to cysteine conjugates, and renal cysteine conjugate beta-lyase in the pathogenesis of Compound A nephrotoxicity was investigated in the rat. Following intraperitoneal administration of Compound A (1 mmol/kg), the presence of bile of two types of Compound A-glutathione conjugates, and the urinary excretion of two types of Compound A-mercapturic acid conjugates, was demonstrated by ionspray-tandem mass spectrometry. Aminooxyacetic acid, a competitive inhibitor of renal cysteine conjugate beta-lyase, partially protected against Compound A-induced diuresis and proteinuria. These results suggest that glutathione conjugate formation, subsequent processing to cysteine conjugates, and cysteine conjugate metabolism by renal beta-lyase may be important factors in the pathogenesis of Compound A-mediated nephrotoxicity in rats.
Jin
L
L
Department of Anesthesiology, University of Washington, Seattle 98195, USA.
Baillie
T A
TA
Davis
M R
MR
Kharasch
E D
ED
D000818:Animals; D013437:Carbon-Sulfur Lyases; D003545:Cysteine / Q000378:metabolism*; D004987:Ethers / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008190:Lyases / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008738:Methyl Ethers; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane
D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019971:cysteine lyase; D005978:Glutathione; D003545:Cysteine