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Vol. 26, Issue 1, 12-19, January 1998
Department of Pharmacology, Wayne State University School of
Medicine (L.H.L., W.Q., D.A.P., K.J.),
Department of Comparative
Biosciences, University of Wisconsin School of Veterinary Medicine
(A.A.E., R.J.K.), and
National Center for Environmental Assessment,
U.S. Environmental Protection Agency (J.C.P.)
Glutathione (GSH) conjugation of trichloroethylene (Tri) to form
S-(1,2-dichlorovinyl)glutathione (DCVG) has been implicated in the nephrotoxicity and nephrocarcinogenicity of Tri. Marked sex- and
species-dependent differences exist, however, in the susceptibility
to Tri-induced renal toxicity, with the male rat being the most
susceptible. The present study, therefore, focuses on potential
differences in the initial step of the GSH pathway. Rates of DCVG
formation were measured in suspensions of isolated renal cortical cells
and isolated hepatocytes from male and female Fischer 344 rats and in
kidney and liver microsomes and cytosol from male and female Fischer
344 rats and B6C3F1 mice to determine if sex- and species-dependent
differences in GSH conjugation correlate with susceptibility to renal
toxicity from Tri. Rates of 
-glutamyltransferase (GGT) with
-glutamyl-p-nitroanilide and glycylglycine as substrates and GSH S-transferase (GST) with
1-chloro-2,4-dinitrobenzene as substrate were also measured in liver
and kidney subcellular fractions to provide further information on the
biochemical basis of susceptibility to Tri. Rates of DCVG formation in
rat kidney cells and kidney subcellular fractions were 5- to 20-fold
lower than those in rat hepatocytes and liver subcellular fractions.
Rates of DCVG formation in kidney cells and subcellular fractions were
comparable in male and female rats with the exception of male rat
kidney microsomes, where DCVG formation was below the limit of
detection, and those in liver cells and subcellular fractions were
>3-fold higher in male rats than in female rats. Rates of DCVG
formation in mouse kidney subcellular fractions were approximately
10-fold higher than in corresponding fractions from the rat, whereas
those in mouse liver subcellular fractions were 4- to 8-fold higher
than in corresponding rat tissues, with rates in male mouse liver
cytosol and microsomes being modestly higher than in corresponding
fractions from female mice. GGT activity was barely detectable in
livers, was about 20-fold higher in rat kidneys than in mouse kidneys, and was slightly higher in female rat kidneys than in male rat kidneys.
GST activity with 1-chloro-2,4-dinitrobenzene as substrate exhibited
tissue-, sex-, and species-dependent patterns that were generally
similar to those with Tri as the substrate. These results suggest that
the higher susceptibility to Tri-induced renal toxicity of male rats as
compared with female rats correlates with rates of DCVG formation. The
high rates of DCVG formation in mice, however, indicate that other
factors, possibly including differences in activities of cysteine
conjugate 
-lyase or N-acetyltransferase, may also be
important determinants of the susceptibility to Tri.
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