ISSN:
1438-8359
Keywords:
Anesthetics
;
Volatile
;
Sevoflurane
;
Toxicity
;
Compound A
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract 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 β-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 mediaited by cytochrome P-450. Injury may result from direct toxicity of compound A or by an undetermined metabolic pathway.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF02480002
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