Metabolism of compound A by renal cysteine-S-conjugate β-lyase is not the mechanism of compound A-induced renal injury in the rat

J. L. Martin, M. J. Laster, L. Kandel, R. L. Kerschmann, G. F. Reed, E. I. Eger

Research output: Contribution to journalArticlepeer-review

Abstract

Compound A [CF2=C(CF3)OCH2F], a vinyl ether produced by CO2 absorbents acting on sevoflurane, can produce corticomedullary junction necrosis (injury to the outer stripe of the outer medullary layer, i.e., corticomedullary junction) in rats. Several halogenated alkenes produce a histologically similar corticomedullary necrosis by converting glutathione conjugates of these alkenes to halothionoacetyl halides. To test whether this mechanism explained the nephrotoxicity of Compound A, we blocked three metabolic steps which would lead to formation of a halothionoacetyl halide: 1) we depleted glutathione by administering dl-buthionine-S,R-sulfoximine (BSO); 2) we blocked cysteine S-conjugate formation by administering acivicin (AT-125); and 3) we inhibited subsequent metabolism by renal cysteine conjugate β- lyase to the nephrotoxic halothionoacetyl halides by administering aminooxyacetic acid (AOAA). These treatments were given alone or in combination to separate groups of 10 or 20 Wistar rats before their exposure to Compound A. We hypothesized that blocking these metabolic steps should decrease the injury produced by breathing 150 ppm of Compound A for 3 h. However, we found either no change or an increase in renal injury, suggesting that this pathway mediates detoxification rather than toxicity. Our findings suggest that the cysteine-S-conjugate-mediated pathway is not the mechanism of Compound A nephrotoxicity and, therefore, observed interspecies differences in the activity of this activating pathway may not be relevant in the prediction of the nephrotoxic potential of Compound A in clinical practice.

Original languageEnglish (US)
Pages (from-to)770-774
Number of pages5
JournalAnesthesia and analgesia
Volume82
Issue number4
DOIs
StatePublished - Apr 19 1996

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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