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 β-Lyase

doi:10.1006/bbrc.1995.1688

Biochemical and Biophysical Research Communications

Volume 210, Issue 2, 16 May 1995, Pages 498-506

https://doi.org/10.1006/bbrc.1995.1688 Get rights and content

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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2003, Toxicology and Applied Pharmacology
Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) is a fluorinated alkene formed by degradation of the volatile anesthetic sevoflurane in anesthesia machines. FDVE is nephrotoxic in rats but not humans. Rat FDVE nephrotoxicity is attributed to FDVE glutathione conjugation and bioactivation of subsequent FDVE-cysteine S-conjugates, in part by renal β-lyase. Although FDVE conjugation and metabolism occur in both rats and humans, the mechanism for selective toxicity in rats and lack of effect in humans is incompletely elucidated. This investigation measured FDVE S-conjugate cytotoxicity in cultured human proximal tubular HK-2 cells, and compared this with known cytotoxic S-conjugates. HK-2 cells were incubated with FDVE and its GSH, cysteine S-mercapturic acid, cysteine S-sulfoxide, and mercapturic acid sulfoxide conjugates (0.1–2.7 mM) for 24 h. Cytotoxicity was determined by lactate dehydrogenase (LDH) release, total LDH, and the ability of viable cells to reduce a tetrazolium-based compound (MTT). FDVE was cytotoxic only at concentrations ≥0.9 mM. No increase in LDH release was observed with either FDVE-GSH conjugate. The FDVE-cysteine conjugates S-(1,1-difluoro-2-fluoromethoxy-2-(trifluoromethyl) ethyl)-l-cysteine (DFEC) and (Z)-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-l-cysteine ((Z)-FFVC) caused significant differences in LDH release and MTT reduction only at 2.7 mM; (Z)-FFVC was slightly more cytotoxic. Both S-(1,1-difluoro-2-fluoromethoxy-2-(trifluoromethyl) ethyl)-l-cysteine sulfoxide (DFEC-SO) and (Z)-N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-l-cysteine sulfoxide ((Z)-N-Ac-FFVC-SO) caused slightly greater changes in LDH release or total LDH than the corresponding equimolar DFEC and (Z)-N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-l-cysteine ((Z)-N-Ac-FFVC) conjugates. In contrast to FDVE S-conjugates, S-(1,2-dichlorovinyl)-l-cysteine was markedly cytotoxic, at concentrations as low as 0.1 mM. These results show that human proximal tubular cells are relatively resistant to FDVE and FDVE S-conjugate cytotoxicity. This may partially explain the lack of FDVE nephrotoxicity in humans.
Biosynthesis of toxic glutathione conjugates from halogenated alkenes
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Glutathione conjugation has been identified as an important detoxication reaction. However, several glutathione-dependent bioactivation reactions have been identified. Current knowledge on the mechanisms and the possible biological importance of these reactions is discussed in this article. Several polychlorinated alkenes are bioactivated in a complex, glutathione-dependent pathway. The first step is hepatic glutathione S-conjugate formation followed by cleavage to the corresponding cysteine S-conjugates, and, after translocation to the kidney, metabolism by renal cysteine conjugate β-lyase. β-Lyase-dependent metabolism of halovinyl cysteine S-conjugates yields electrophilic thioketenes, whose covalent binding to cellular macromolecules is likely responsible for the observed nephrotoxicity of the parent compounds.
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2003, Best Practice and Research: Clinical Anaesthesiology
The halogenated inhalational anaesthetics halothane, enflurane, isoflurane and desflurane can produce metabolic hepatocellular injury in humans to a variable extent. During metabolism of these anaesthetics, tissue acetylation occurs due to the formation of reactive intermediates. Proteins modified by acetylation may constitute neo-antigens with a potential for triggering an antibody-mediated immune response. The likelihood of suffering post-operative immune hepatitis depends on the amount of the anaesthetic metabolized and is thereby considerably less with enflurane, isoflurane or desflurane compared with halothane. Plasma inorganic fluoride concentrations are regularly increased after sevoflurane. Elevated inorganic fluoride concentrations have been associated with nephrotoxicity following methoxyflurane anaesthesiabut not after sevoflurane. Another source of concern is the products of degradation from reactions with carbon dioxide absorbents. Most important is compound A, which has been shown to exhibit nephrotoxicity in rodents. However, no significant changes in renal function parameters have been reported in surgical patients.
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Glutathione S-conjugation of the sevoflurane degradation product, fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (Compound A) in human liver, kidney, and blood in vitro
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Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) is a fluorinated alkene formed by degradation of the volatile anesthetic sevoflurane in anesthesia machines. FDVE is nephrotoxic in rats and undergoes glutathione-dependent conjugation to form two alkane (G1, G2) and two alkene glutathione S-conjugates (G3, G4), cleavage to cysteine S-conjugates, and β-lyase-catalyzed metabolism to reactive thionoacyl fluorides, which may react with cellular macromolecules to cause nephrotoxicity. Although similar metabolites have been identified in human urine in vivo, little is known about sites and mechanisms of GSH conjugation in humans. This investigation quantified FDVE–GSH conjugates formed by human hepatic and renal microsomal and cytosolic fractions and blood in vitro. LC–MS/MS analysis identified all four GSH conjugates (G1–G4) formed in all human subcellular fractions. Quantitative analysis indicated that the relative order of formation was G2 > G1 > G4 > G3 with human liver and kidney subfractions. In blood, the order was G1 > G4 > G2 > G3. These results demostrate that FDVE undergoes GSH-dependent conjugation in human liver and kidney microsomes and cytosol as well as blood, which may account for the detection of corresponding mercapturic acids in the urine of patients exposed to FDVE.

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Regular ArticleNephrotoxicity 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 β-Lyase

Abstract

Regular Article
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 β-Lyase