Characterization of Thioether Compounds Formed from Alkaline Degradation Products of Enflurane

Hilmi Orhan, Nico P. E. Vermeulen, Gonul Sahin, Jan N. M. Commandeur
2001 Anesthesiology  
Renal toxicity has occasionally been observed after enflurane anesthesia. Although originally attributed to its oxidative metabolism to inorganic fluoride, serum levels of inorganic fluoride appear to be small to explain these renal effects. Formation of potentially nephrotoxic halogenated alkenes during alkaline degradation in carbon dioxide absorbers and subsequent bioactivation via the glutathione conjugation pathway may be considered as an alternative mechanism for renal toxicity. The aim
more » ... this study was to characterize the thioethers formed chemically and biosynthetically. Methods: Alkaline degradation of enflurane was achieved by stirring with pulverized potassium hydroxide. Volatile degradation products were analyzed by 19 F nuclear magnetic resonance (NMR) analysis of head space gasses trapped in dimethyl sulfoxide (DMSO). Thioethers were generated chemically by trapping head space gasses in DMSO containing N-acetyl-L-cysteine or 2-mercaptoacetic acid as model thiol compounds. Glutathione conjugates were generated biosynthetically by passing head space through rat liver fractions in presence of glutathione. Products formed were analyzed by gas chromatographymass spectroscopy and 19 F-NMR. Results: Direct analysis of head space gasses showed formation of 1-chloro-1,2-difluorovinyl difluoromethyl ether and two unidentified fluorine-containing products as alkaline degradation products of enflurane. When trapped in DMSO-N-acetyl-Lcysteine-triethylamine, N-acetyl-S-(2-chloro-1,2-difluoro-1-(difluoromethoxy)ethyl)-L-cysteine was identified as the major product. Another N-acetyl-L-cysteine S-conjugate formed was N-acetyl-S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine, a potent nephrotoxin in rats. 19 F-NMR analysis of glutathione conjugates formed after incubation with rat liver fractions resulted in formation of corresponding S-conjugates. Conclusions: The current study demonstrates that alkaline degradation products of enflurane can be conjugated to thiol compounds, forming S-conjugates that could theoretically contribute to adverse renal effects observed occasionally with enflurane anesthesia. The N-acetyl-L-cysteine S-conjugates identified may be biomarkers to assess exposure of humans to alkaline degradation products of enflurane. . Address electronic mail to: command@chem.vu.nl. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org. Anesthesiology, V 95, No 1, Jul 2001 166 ORHAN ET AL. Anesthesiology, V 95, No 1, Jul 2001 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931226/ on 08/17/2017 * Labels refer to fluorine atoms as indicated in figure 5. † Solvent: deuterium oxide; parts per million (ppm) relative to trifluoroacetic acid. 19 F-NMR ϭ 19 F nuclear magnetic resonance; d ϭ doublet; t ϭ triplet.
doi:10.1097/00000542-200107000-00027 pmid:11465554 fatcat:thvrwydyt5hv5fcq3pky5ltwny