Fourier-transform ion cyclotron resonance mass spectrometric studies of elimination reactions of anionic bases with metabolites of a fluorinated anesthetic agent: towards modeling bioactivation in the gas phase
Nc. Luu et al., Fourier-transform ion cyclotron resonance mass spectrometric studies of elimination reactions of anionic bases with metabolites of a fluorinated anesthetic agent: towards modeling bioactivation in the gas phase, INT J MASS, 196, 2000, pp. 203-213
Sevoflurane (fluoromethyl 2,2,2-trifluoro-[2,2,2-trifluoromethyl]ethyl ethe
r) is a volatile anesthetic agent that is widely used in the U.S. and abroa
d. Sevoflurane undergoes degradation in the anesthetic circuit to form 2-(f
luoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A). As it is metabo
lized, Compound A alkylates the cysteine side chain in the tripeptide gluta
thione, which acts as a sort of scavenger for xenobiotics such as Compound
A. The S-alkylated glutathione or glutathione S conjugate loses its C-termi
nal and N-terminal residues as it is further metabolized. This leaves a cys
teine S conjugate of Compound A. The cysteine conjugate undergoes bioactiva
tion by an enzyme known as beta-lyase to produce nephrotoxic metabolites. A
lthough Compound A is nephrotoxic in rats, Compound A-associated nephrotoxi
city has not been observed in the human clinical use of sevoflurane, appare
ntly because beta-lyase activities are much lower in human kidney tissue th
an in rat kidney tissue. Since beta-lyase reacts with carbonyl compounds by
mechanisms involving deprotonation of the alpha-carbon, the reactions of C
ompound A-derived cysteine conjugates with the basic anionic species hydrox
ide, methoxide, and ethoxide were examined by Fourier-transform ion cyclotr
on resonance mass spectrometry. The anionic bases examined react with the c
ysteine conjugates by an initial deprotonation of the alpha-carbon to form
an enolate intermediate followed by elimination of either a thiolate anion
or of HF. Since the HF elimination leads to CF2 loss, it is suggested that
the F atom eliminated as HF comes from a CF2 group. Collision-induced disso
ciation (CID) of the product ions suggested structures consistent with this
overall mechanistic picture. It is evident from these results that the sam
e mechanism by which other cysteine conjugates are bioactivated could opera
te in the case of Compound A. That is, deprotonation to form enolate interm
ediates could lead to the release of very reactive species that might inact
ivate enzymes by alkylating them or otherwise reacting irreversibly with th
em. The thiolate product could alkylate an enzyme under appropriate conditi
ons. Condensed-phase hydrolysis of the thiolate product could produce 2-(fl
uoromethoxy)-3,3,3-trifluoropropionic acid, a known metabolite of Compound
A. The HF loss channel produces not only HF, but also CF2, a very reactive
species, Evidence is noted that a closely related enzyme substrate system r
eacts to release fluoride in condensed phases suggesting that the activatio
n of a CF3 observed here could be a more general process, (C) 2000 Elsevier
Science B.V.