Abstract
Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE; 1) is a fluoroalkene formed by the base-catalyzed degradation of the anesthetic sevoflurane. FDVE is nephrotoxic in rats. In both rats and humans, FDVE undergoes glutathione-dependent conjugation, cleavage to cysteine S-conjugates, and renal β-lyase-catalyzed metabolism to reactive intermediates, which may cause nephrotoxicity. Interindividual variability in renal metabolism of FDVE is unknown. Therefore, this investigation quantified β-lyase-catalyzed bioactivation and N-acetyltransferase-catalyzed inactivation of FDVE cysteine S-conjugates and reactivation of mercapturates by N-deacetylase in cytosol and microsomes from 20 human kidneys. In cytosol,N-acetylation ranged from 0.008 to 0.045 (0.024 ± 0.01) nmol of mercapturate/mg/min and 0.001 to 0.07 (0.024 ± 0.02) nmol of mercapturate/mg/min for alkane and alkene cysteineS-conjugates, respectively. Similar results for microsomal N-acetylation were obtained;N-acetylation ranged from 0.005 to 0.055 (0.025 ± 0.02) nmol of mercapturate/mg/min and 0.001 to 0.06 (0.030 ± 0.02) nmol of mercapturate/mg/min for alkane and alkene cysteineS-conjugates, respectively. β-Lyase-catalyzed metabolism to pyruvate varied from 0.004 to 0.14 (0.051 ± 0.04) nmol/mg/min and from 0.10 to 0.40 (0.26 ± 0.08) nmol/mg/min for alkane and alkene cysteine-S-conjugates, respectively.N-deacetylation of mercapturates ranged from 0.8 to 2.5 (1.25 ± 0.57) nmol of cysteine S-conjugate formed/mg/min and 0.05 to 0.37 (0.17 ± 0.10) nmol of cysteineS-conjugate formed/mg/min for alkane and alkene FDVE mercapturates. Cytosolic cysteine S-conjugates metabolism by renal β-lyase predominated overN-acetylation (ratio of activities was 0.2–6 and 3–146 for the alkane and alkene cysteine S-conjugates).N-deacetylation predominated overN-acetylation (ratio of activities was 20–205 and 2–54 for alkane and alkene S-conjugates). There was considerable (up to 50-fold) interindividual variability in rates of FDVE toxication (β-lyase metabolism andN-deacetylation) and detoxication. This interindividual variability may effect individual susceptibility to the nephrotoxicity of FDVE and other haloalkenes.
Footnotes
-
This study was supported by National Institutes of Health Grant R01 DK53765.
- Abbreviations used are::
- FDVE
- fluoromethyl-2,2-difluoro-1-(trifluoromethyl) vinyl ether
- GSH
- glutathione
- LC/MS
- liquid chromatography/mass spectrometry
- GS/MS
- gas chromatography/mass spectrometry
- HKC
- human kidney cytosol
- Received July 17, 2001.
- Accepted November 9, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|