Toxicological Sciences, Vol 48, 5-13, Copyright © 1999 by Society of Toxicology
A Pahler, J Parker and W Dekant
Perchloroethene (PER) was a widely used solvent and is an environmental
contaminant. In bioassays for carcinogenicity, PER was found to increase
the incidence of liver tumors in mice and of renal tumors in male rats.
Toxic effects of PER after repeated administration are likely caused by
bioactivation. PER bioactivation occurs by two pathways. Oxidation by
cytochrome P450 results in trichloroacetyl chloride, which binds to lipids
and proteins. Glutathione S-conjugate formation from PER and further
processing of the formed S- (trichlorovinyl)glutathione to
S-(trichlorovinyl)-L-cysteine, followed by cysteine conjugate beta-lyase
catalyzed cleavage, resulted in the reactive dichlorothioketene, which
binds to proteins under formation of N epsilon-(dichloroacetyl)-L-lysine in
proteins. The objective of this study was to comparatively quantify the
dose-dependent formation of protein adducts from PER in rats and humans
using antibodies with high specificity for either N
epsilon-(trichloroacetyl)-L-lysine or N epsilon-(dichloroacetyl)-L-lysine
in proteins. Male and female rats (n = 2, per concentration and time point)
were exposed to 400, 40, and 10 ppm PER for 6 h and killed at various time
points. Formation of N epsilon-(dichloroacetyl)-L-lysine and N
epsilon-(trichloroacetyl)-L- lysine in proteins was comparatively
quantified in subcellular fractions from liver and kidney and in blood. In
addition, three male and three female human volunteers were exposed to 10
and 40 ppm PER, and formation of protein adducts in blood was analyzed
using the antibodies and GC/MS after immunoaffinity enrichment of modified
proteins. In liver and kidney subcellular fractions and blood of PER-
exposed rats, dose-dependent formation of N epsilon-(dichloroacetyl)-L-
lysine and N epsilon-(trichloroacetyl)-L-lysine in proteins was observed.
Highest concentrations of N epsilon-(dichloroacetyl)-L-lysine in proteins
were formed in kidney mitochondria, followed by kidney cytosol. Only low
concentrations of N epsilon-(dichloroacetyl)-L-lysine in proteins were
present in liver proteins; blood concentrations of N
epsilon-(dichloroacetyl)-L-lysine in proteins were 5 to 10 fold lower than
in kidney mitochondria. Highest concentrations of N epsilon-
(trichloroacetyl)-L-lysine were found in microsomal and cytosolic proteins
from the liver of rats exposed to PER. A higher protein adduct formation
was seen in PER-exposed-male than -female rats for N epsilon-
(dichloroacetyl)-L-lysine in renal mitochondrial proteins, after exposure
to 400 ppm PER. In human blood samples taken 0 and 24 h after the 6 h
exposures to PER, N epsilon-(trichloroacetyl)-L-lysine- containing proteins
were present in low concentrations. N epsilon-
(Dichloroacetyl)-L-lysine-containing proteins were not detected either by
Western blotting or GC/MS after immunoaffinity chromatography. The obtained
results indicate a dose-dependent covalent binding of PER metabolites to
proteins in rat liver, kidney, and blood and suggest that the concentration
of covalent protein adducts is much lower in blood of humans as compared to
the blood of rats exposed under identical conditions.
ARTICLES
Dose-dependent protein adduct formation in kidney, liver, and blood of rats and in human blood after perchloroethene inhalation
Institut fur Toxikologie, Universitat Wurzburg, Germany.
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