Studies of the mechanism of nephrotoxicity of compound A in rats

CO₂ absorbents acting on sevoflurane produce compound A [CF₂ = C(CF₃)OCH₂F]. Rats breathing 25-50 ppm of compound A for 3-12 h demonstrate corticomedullary renal injury. Several halogenated alkenes also produce a well described corticomedullary lesion by conversion of glutathione conjugates of these alkenes to cysteine s-conjugates and subsequent metabolism by renal cysteine conjugate B-lyase to nephrotoxic halothionoacetyl halides. We tested whether a similar mechanism explained the nephrotoxicity of compound A or whether an oxidative metabolism of compound A by cytochrome P-450 was required for the induction of nephrotoxicity. A closed rebreathing system was used and male Wistar rats were exposed for 1 h to: (1) oxygen alone; (2) 800 ppm compound A; (3) 800 ppm compound A after pretreatment with intraperitoneal aminooxyacetic acid (AOAA), 0.5 mmoles/kg, an inhibitor of renal cysteine conjugate β-lyase; (4) 600 ppm compound A; (5) 600 ppm compound A after pretreatment with intraperitoneal AOAA, 0.50 mmoles/kg plus acivicin (AT-125), 0.25 mmoles/kg, an inhibitor of gamma glutamyl transpeptidase; (6) 600 ppm compound A after pretreatment with 1600 mg/kg piperonyl butoxide (PB) subcutaneously, and (7) 600 ppm compound A after pretreatment with 100 mg/kg 1-aminobenzotriazole (ABT) by intraperitoneal injection (both PB and ABT inhibit cytochrome P-450s). All rats were killed 24 h following exposure to compound A or oxygen, or to pretreatments without compound A, and the kidneys were collected for histological analysis. Pretreatments given without compound A did not cause renal injury. Necrosis was found in 20.9 ± 16.7% (mean ± SD) of corticomedullary tubule cells following exposure of Wistar rats to 600 ppm compound A. Pretreatment with AOAA plus AT-125 increased necrosis to 57.9 ± 32.6%, (P < 0.005). PB or ABT given prior to compound A increased corticomedullary injury to 39.0 ± 31.4% (P < 0.02) and 51.2 ± 31.8% (P < 0.025), respectively. In rats exposed to 800 ppm compound A, pretreatment with AOAA increased necrosis from 63.8 ± 30.1% to 81.2 ± 27.7% (P < 0.1). Unlike many other halogenated alkenes, compound A does not appear to produce renal injury by conversion of a cysteine S-conjugate to a toxic thiol, nor does injury require metabolism mediated by cytochrome P-450. Injury may result from direct toxicity of compound A or by an undetermined metabolic pathway.