METABOLISM OF COMPOUND-A BY RENAL CYSTEINE-S-CONJUGATE BETA-LYASE IS NOT THE MECHANISM OF COMPOUND-A-INDUCED RENAL INJURY IN THE RAT

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., corti comedullary junction) in rats. Several halogenated alkenes produce a h istologically similar corticomedullary necrosis by converting glutathi one conjugates of these alkenes to halothionoacetyl halides. To test w hether this mechanism explained the nephrotoxicity of Compound A, we b locked three metabolic steps which would lead to formation of a haloth ionoacetyl halide: 1) we depleted glutathione by administering dl-buth ionine-S,R-sulfoximine (BSO); 2) we blocked cysteine S-conjugate forma tion by administering acivicin (AT-125); and 3) we inhibited subsequen t metabolism by renal cysteine conjugate beta-lyase to the nephrotoxic acetic acid (AOAA). These treatments were given alone or in combinati on to separate groups of 10 or 20 Wistar rats before their exposure to Compound A. We hypothesized that blocking these metabolic steps shoul d 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 tox icity. Our findings suggest that the cysteine-S-conjugate-mediated pat hway 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 poten tial of Compound A in clinical practice.