Bioactivation mechanism of the cytotoxic and nephrotoxic S-conjugate S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine

Journal Article · Sat Oct 31 23:00:00 EST 1987 · Proc. Natl. Acad. Sci. U.S.A.; (United States)

DOI:https://doi.org/10.1073/pnas.84.21.7443· OSTI ID:6837861

Dekant, W; Lash, L H; Anders, M W

The bioactivation of S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (CTFC) was studied with purified bovine kidney cysteine conjugate ..beta..-lyase and with N-dodecylpyridoxal bromide in cetyltrimethylammonium bromide micelles as a pyridoxal model system. The ..beta..-lyase and the pyridoxal model system converted CTFC to chlorofluoroacetic acid and inorganic fluoride, which were identified by /sup 19/F NMR spectrometry. 2-Chloro-1,1,2-trifluoroethanethiol and chlorofluorothionoacetyl fluoride were formed as metabolites of CTFC and were trapped with benzyl bromide and diethylamine, respectively, to yield benzyl 2-chloro-1,1,2-trifluoroethyl sulfide and N,N-diethyl chlorofluorothioacetamide, which were identified by gas chromatography/mass spectrometry. The bioactivation mechanism of CTFC therefore involves the initial formation of the unstable thiol 2-chloro-1,1,2-trifluoroethanethiol, which loses hydrogen fluoride to form the acylating agent chlorofluorothionoacetyl fluoride; hydrolysis of the thionoacyl fluoride affords the stable, terminal metabolites chlorofluoroacetic acid and inorganic fluoride. The intermediate acylating agent and chlorofluoroacetic acid may contribute to the cytotoxic effects of CTFC.

• Research Organization: Univ. of Rochester, NY (USA)
• OSTI ID: 6837861
• Journal Information: Proc. Natl. Acad. Sci. U.S.A.; (United States), Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States) Vol. 84:21; ISSN PNASA
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
ALKYLATING AGENTS
AMINO ACIDS
BARYONS
BIOLOGICAL PATHWAYS
BODY
CARBOXYLIC ACIDS
CHEMICAL SHIFT
CYSTEINE
ELEMENTARY PARTICLES
ENZYMES
FERMIONS
FLUORINE 19
FLUORINE ISOTOPES
HADRONS
ISOTOPES
KIDNEYS
LIGHT NUCLEI
LYASES
MAGNETIC RESONANCE
METABOLIC ACTIVATION
METABOLITES
NUCLEAR MAGNETIC RESONANCE
NUCLEI
NUCLEONS
ODD-EVEN NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
PROTONS
RESONANCE
STABLE ISOTOPES
THIOLS
XENOBIOTICS