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 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 32-37 |
| Number of pages | 6 |
| Journal | Journal of Anesthesia |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1997 |
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Keywords
- Anesthetics
- Compound A
- Sevoflurane
- Toxicity
- Volatile
ASJC Scopus subject areas
- Anesthesiology and Pain Medicine
Cite this
Studies of the mechanism of nephrotoxicity of compound A in rats. / Martin, J. L.; Kandel, L.; Laster, M. J.; Kerschmann, R. L.; Eger, E. I.
In: Journal of Anesthesia, Vol. 11, No. 1, 1997, p. 32-37.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Studies of the mechanism of nephrotoxicity of compound A in rats
AU - Martin, J. L.
AU - Kandel, L.
AU - Laster, M. J.
AU - Kerschmann, R. L.
AU - Eger, E. I.
PY - 1997
Y1 - 1997
N2 - 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.
AB - 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.
KW - Anesthetics
KW - Compound A
KW - Sevoflurane
KW - Toxicity
KW - Volatile
UR - http://www.scopus.com/inward/record.url?scp=0030950971&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030950971&partnerID=8YFLogxK
U2 - 10.1007/BF02480002
DO - 10.1007/BF02480002
M3 - Article
C2 - 28921267
AN - SCOPUS:0030950971
VL - 11
SP - 32
EP - 37
JO - Journal of Anesthesia
JF - Journal of Anesthesia
SN - 0913-8668
IS - 1
ER -