Abstract
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 β-lyase in the pathogenesis of Compound A nephrotoxicity was investigated in the rat. Following intraperitoneal administration of Compound A (1 mmol/kg), the presence in 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 β-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 β-lyase may be important factors in the pathogenesis of Compound A-mediated nephrotoxicity in rats.
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