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Journal of Pharmacology and Experimental Therapeutics

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OtherTOXICOLOGY

Nephrotoxicity of the Glutathione and CysteineS-Conjugates of the Sevoflurane Degradation Product 2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A) in Male Fischer 344 Rats

Ramaswamy A. Iyer, Raymond B. Baggs and M. W. Anders
Journal of Pharmacology and Experimental Therapeutics December 1997, 283 (3) 1544-1551;
Ramaswamy A. Iyer
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Raymond B. Baggs
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M. W. Anders
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Abstract

2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A) is a halogenated alkene that is nephrotoxic in rats when administered by inhalation or intraperitoneally. Compound A undergoes glutathione-dependent metabolism: Compound A-derived glutathioneS-conjugates and mercapturates are excreted in the bile and urine, respectively, of rats given Compound A. The present experiments were designed to study the nephrotoxicity of the Compound A-derived glutathione and cysteine S-conjugates,S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]glutathione2,S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]glutathione3,S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-l-cysteine4 andS-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-l-cysteine5. Conjugates 2, 3 and 4given intraperitoneally produced dose-dependent nephrotoxicity that was characterized by diuresis, increased excretion of glucose and protein, elevated blood urea nitrogen concentrations and severe morphological changes in the kidneys, particularly in the proximal tubules. Glutathione S-conjugate 2, at a dose of 500 μmol/kg, was hepatotoxic. Cysteine S-conjugate5 was not nephrotoxic, apparently because of its facile cyclization to the thiazoline 2-[1-(fluoromethoxy)-2,2,2-trifluoroethyl]-4,5-dihydro-1,3-thiazole-4-carboxylic acid, which is not a β-lyase substrate. Also, the α-methyl analog of cysteine S-conjugate 4S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-dl-α-methylcysteine, which cannot undergo β-lyase-dependent bioactivation, was not nephrotoxic. These in vivo data show that Compound A-derived S-conjugates are nephrotoxic and that the toxicity is associated with β-lyase-dependent bioactivation.

Footnotes

  • Send reprint requests to: M. W. Anders, Department of Pharmacology and Physiology, University of Rochester, 601 Elmwood Ave., Box 711, Rochester, NY 14642.

  • ↵1 This research was supported by Abbott Laboratories and by the National Institute of Environmental Health Sciences grant ES03127 (to M.W.A.).

    • Received February 25, 1997.
    • Accepted August 5, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 3
1 Dec 1997
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Nephrotoxicity of the Glutathione and CysteineS-Conjugates of the Sevoflurane Degradation Product 2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A) in Male Fischer 344 Rats
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OtherTOXICOLOGY

Nephrotoxicity of the Glutathione and CysteineS-Conjugates of the Sevoflurane Degradation Product 2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A) in Male Fischer 344 Rats

Ramaswamy A. Iyer, Raymond B. Baggs and M. W. Anders
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1544-1551;

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OtherTOXICOLOGY

Nephrotoxicity of the Glutathione and CysteineS-Conjugates of the Sevoflurane Degradation Product 2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A) in Male Fischer 344 Rats

Ramaswamy A. Iyer, Raymond B. Baggs and M. W. Anders
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1544-1551;
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