Toxicity of a sevoflurane degradation product incubated with rat liver and renal cortical slices

J. M. Catania, A. R. Parrish, A Jay Gandolfi

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Compound A (2-fluoromethoxy-1,1,3,3,3-pentafluoro-1-propene) is a degradation product of the anesthetic sevoflurane which is created in closed-circuit anesthetic machines. Past in vivo and in vitro studies have implied that Compound A is nephrotoxic via bioactivation through the cysteine conjugate β-lyase pathway. Although glutathione (GSH) conjugates of Compound A have been reported, it is not clear if they are formed enzymatically or via direct reaction with GSH. To determine if these metabolites are produced and toxic, a tissue slice system that first exposes male Fischer 344 rat liver slices to volatilized Compound A followed by exposure of rat kidney slices to the liver incubate was employed. Liver slices exposed to volatilized Compound A (6-12 μM medium conc.; ∼23 ppm) exhibited a loss of K+ by 6 h, which was not seen in kidney slices exposed to Compound A. Aminobenzotriazole, a cytochrome P 450 suicide inhibitor, initially inhibits the cytotoxicity of Compound A to liver slices (at these times and concentrations). The sequential liver/kidney slice experiments using Compound A have not demonstrated nephrotoxic results. GSH conjugates were synthesized and was found to be nephrotoxic at concentrations above 91 μM (18 h), with higher concentrations showing toxicity at earlier times. Additionally, non-enzymatic reactions of Compound A with GSH or sulfhydryl-containing medium produces nephrotoxic products. These studies show that Compound A is directly toxic to the liver, possibly via P 450 activation, and Compound A can react with sulfhydryls directly to produce a nephrotoxic.

Original languageEnglish (US)
Pages (from-to)347-357
Number of pages11
JournalDrug and Chemical Toxicology
Volume24
Issue number4
DOIs
StatePublished - 2001

Fingerprint

Liver
Toxicity
Rats
Kidney
Degradation
Anesthetics
Poisons
Lyases
compound A 12
Inbred F344 Rats
Cytotoxicity
Metabolites
Suicide
Propylene
Glutathione
Cysteine
sevoflurane
Chemical activation
Tissue
Networks (circuits)

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmacology
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Toxicity of a sevoflurane degradation product incubated with rat liver and renal cortical slices. / Catania, J. M.; Parrish, A. R.; Gandolfi, A Jay.

In: Drug and Chemical Toxicology, Vol. 24, No. 4, 2001, p. 347-357.

Research output: Contribution to journalArticle

@article{ad20483839004392806d6d2ee480167c,
title = "Toxicity of a sevoflurane degradation product incubated with rat liver and renal cortical slices",
abstract = "Compound A (2-fluoromethoxy-1,1,3,3,3-pentafluoro-1-propene) is a degradation product of the anesthetic sevoflurane which is created in closed-circuit anesthetic machines. Past in vivo and in vitro studies have implied that Compound A is nephrotoxic via bioactivation through the cysteine conjugate β-lyase pathway. Although glutathione (GSH) conjugates of Compound A have been reported, it is not clear if they are formed enzymatically or via direct reaction with GSH. To determine if these metabolites are produced and toxic, a tissue slice system that first exposes male Fischer 344 rat liver slices to volatilized Compound A followed by exposure of rat kidney slices to the liver incubate was employed. Liver slices exposed to volatilized Compound A (6-12 μM medium conc.; ∼23 ppm) exhibited a loss of K+ by 6 h, which was not seen in kidney slices exposed to Compound A. Aminobenzotriazole, a cytochrome P 450 suicide inhibitor, initially inhibits the cytotoxicity of Compound A to liver slices (at these times and concentrations). The sequential liver/kidney slice experiments using Compound A have not demonstrated nephrotoxic results. GSH conjugates were synthesized and was found to be nephrotoxic at concentrations above 91 μM (18 h), with higher concentrations showing toxicity at earlier times. Additionally, non-enzymatic reactions of Compound A with GSH or sulfhydryl-containing medium produces nephrotoxic products. These studies show that Compound A is directly toxic to the liver, possibly via P 450 activation, and Compound A can react with sulfhydryls directly to produce a nephrotoxic.",
author = "Catania, {J. M.} and Parrish, {A. R.} and Gandolfi, {A Jay}",
year = "2001",
doi = "10.1081/DCT-100106264",
language = "English (US)",
volume = "24",
pages = "347--357",
journal = "Drug and Chemical Toxicology",
issn = "0148-0545",
publisher = "Informa Healthcare",
number = "4",

}

TY - JOUR

T1 - Toxicity of a sevoflurane degradation product incubated with rat liver and renal cortical slices

AU - Catania, J. M.

AU - Parrish, A. R.

AU - Gandolfi, A Jay

PY - 2001

Y1 - 2001

N2 - Compound A (2-fluoromethoxy-1,1,3,3,3-pentafluoro-1-propene) is a degradation product of the anesthetic sevoflurane which is created in closed-circuit anesthetic machines. Past in vivo and in vitro studies have implied that Compound A is nephrotoxic via bioactivation through the cysteine conjugate β-lyase pathway. Although glutathione (GSH) conjugates of Compound A have been reported, it is not clear if they are formed enzymatically or via direct reaction with GSH. To determine if these metabolites are produced and toxic, a tissue slice system that first exposes male Fischer 344 rat liver slices to volatilized Compound A followed by exposure of rat kidney slices to the liver incubate was employed. Liver slices exposed to volatilized Compound A (6-12 μM medium conc.; ∼23 ppm) exhibited a loss of K+ by 6 h, which was not seen in kidney slices exposed to Compound A. Aminobenzotriazole, a cytochrome P 450 suicide inhibitor, initially inhibits the cytotoxicity of Compound A to liver slices (at these times and concentrations). The sequential liver/kidney slice experiments using Compound A have not demonstrated nephrotoxic results. GSH conjugates were synthesized and was found to be nephrotoxic at concentrations above 91 μM (18 h), with higher concentrations showing toxicity at earlier times. Additionally, non-enzymatic reactions of Compound A with GSH or sulfhydryl-containing medium produces nephrotoxic products. These studies show that Compound A is directly toxic to the liver, possibly via P 450 activation, and Compound A can react with sulfhydryls directly to produce a nephrotoxic.

AB - Compound A (2-fluoromethoxy-1,1,3,3,3-pentafluoro-1-propene) is a degradation product of the anesthetic sevoflurane which is created in closed-circuit anesthetic machines. Past in vivo and in vitro studies have implied that Compound A is nephrotoxic via bioactivation through the cysteine conjugate β-lyase pathway. Although glutathione (GSH) conjugates of Compound A have been reported, it is not clear if they are formed enzymatically or via direct reaction with GSH. To determine if these metabolites are produced and toxic, a tissue slice system that first exposes male Fischer 344 rat liver slices to volatilized Compound A followed by exposure of rat kidney slices to the liver incubate was employed. Liver slices exposed to volatilized Compound A (6-12 μM medium conc.; ∼23 ppm) exhibited a loss of K+ by 6 h, which was not seen in kidney slices exposed to Compound A. Aminobenzotriazole, a cytochrome P 450 suicide inhibitor, initially inhibits the cytotoxicity of Compound A to liver slices (at these times and concentrations). The sequential liver/kidney slice experiments using Compound A have not demonstrated nephrotoxic results. GSH conjugates were synthesized and was found to be nephrotoxic at concentrations above 91 μM (18 h), with higher concentrations showing toxicity at earlier times. Additionally, non-enzymatic reactions of Compound A with GSH or sulfhydryl-containing medium produces nephrotoxic products. These studies show that Compound A is directly toxic to the liver, possibly via P 450 activation, and Compound A can react with sulfhydryls directly to produce a nephrotoxic.

UR - http://www.scopus.com/inward/record.url?scp=0034788356&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034788356&partnerID=8YFLogxK

U2 - 10.1081/DCT-100106264

DO - 10.1081/DCT-100106264

M3 - Article

C2 - 11665648

AN - SCOPUS:0034788356

VL - 24

SP - 347

EP - 357

JO - Drug and Chemical Toxicology

JF - Drug and Chemical Toxicology

SN - 0148-0545

IS - 4

ER -