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Vol. 27, Issue 3, 351-359, March 1999
Department of Pharmacology, Wayne State University School of
Medicine, Detroit, Michigan (L.H.L., D.A.P.);
U.S. Air Force, Air Force
Research Laboratory, Toxicology Branch, Wright-Patterson Air Force
Base, Dayton, Ohio (J.C.L.); and
National Center for
Environmental Assessment, U.S. Environmental Protection Agency,
Washington, D.C. (J.C.P.)
Isolated human hepatocytes exhibited time-, trichloroethylene (Tri)
concentration-, and cell concentration-dependent formation of
S-(1,2-dichlorovinyl)glutathione (DCVG) in incubations
in sealed flasks with 25 to 10,000 ppm Tri in the headspace,
corresponding to 0.011 to 4.4 mM in hepatocytes. Maximal formation of
DCVG (22.5 ± 8.3 nmol/120 min per 106 cells) occurred
with 500 ppm Tri. Time-, protein concentration-, and both Tri and GSH
concentration-dependent formation of DCVG were observed in liver and
kidney subcellular fractions. Two kinetically distinct systems were
observed in both cytosol and microsomes from pooled liver samples,
whereas only one system was observed in subcellular fractions from
pooled kidney samples. Liver cytosol exhibited apparent
Km values (µM Tri) of 333 and 22.7 and
Vmax values (nmol DCVG formed/min per mg
protein) of 8.77 and 4.27; liver microsomes exhibited apparent
Km values of 250 and 29.4 and
Vmax values of 3.10 and 1.42; kidney cytosol
and microsomes exhibited apparent Km values
of 26.3 and 167, respectively, and Vmax
values of 0.81 and 6.29, respectively. DCVG formation in samples of
liver cytosol and microsomes from 20 individual donors exhibited a
6.5-fold variation in microsomes but only a 2.4-fold variation in
cytosol. In coincubations of pooled liver cytosol and microsomes,
addition of an NADPH-regenerating system produced marked inhibition of
DCVG formation, but addition of GSH had no effect on cytochrome
P-450-catalyzed formation of chloral hydrate. These results indicate
that both human kidney and liver have significant capacity to catalyze
DCVG formation, indicating that the initial step of the GSH-dependent
pathway is not limiting in the formation of nephrotoxic and
nephrocarcinogenic metabolites.
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