Molecular and Cellular PharmacologyRole of cytochrome P450 and glutathione S-transferase α in the metabolism and cytotoxicity of trichloroethylene in rat kidney
Section snippets
Chemicals
TRI (reported to be 99.9% pure, as judged by electron ionization mass spectrometry), collagenase type IV, bovine serum albumin (fraction V), acivicin [l-(αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid], BSP, l-γ-glutamyl-l-glutamate, and CDNB were purchased from the Sigma Chemical Co. DCVG was synthesized as previously described [34]. Purity (>95%) was determined by HPLC analysis, and identity was confirmed by proton NMR spectroscopy. TETB was purchased from the Aldrich Chemical Co.
Cytotoxicity of TRI in freshly isolated rat renal PT and DT cells
Freshly isolated rat renal PT and DT cells were incubated in the presence of various concentrations of TRI, ranging from 0.1 to 10 mM (data not shown). TRI was modestly cytotoxic to PT and DT cells only at the highest concentration tested (i.e. 10 mM), causing approximately a 20% increase in LDH release, whereas concentrations of TRI of 5 mM or below had no effect on LDH release.
Preincubation of PT and DT cells with metyrapone (0.25 mM), a general P450 inhibitor, increased TRI cytotoxicity in
Discussion
The objective of the present study was to determine differences in TRI cytotoxicity and metabolism between rat renal PT and DT cells and to use these differences to assess factors that are determinants of susceptibility to TRI. Freshly isolated cells were used so that susceptibility and enzyme expression and activity would be similar to that found in the kidneys in vivo. With knowledge of how renal metabolism and handling of TRI and its GSH-derived metabolites differ in rats and humans, these
Acknowledgements
This work was supported by National Institutes of Diabetes and Digestive and Kidney Diseases Grant R01-DK40725 and by a Cooperative Agreement with the U.S. Environmental Protection Agency (CR-824183). The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency.
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Trichloroethylene exposure in mid-pregnancy decreased fetal weight and increased placental markers of oxidative stress in rats
2019, Reproductive ToxicologyCitation Excerpt :Furthermore, our finding of increased expression of GST-pi protein in placenta of TCE-treated rats is consistent with a report that occupational exposure to TCE was associated with increased levels of GST-pi in the urine [51], although Bruning and colleagues found a positive association between exposure to TCE and urinary concentrations of GST-alpha but not GST-pi in a retrospective study [52]. In rat kidney cells, GST-alpha is the primary isoform responsible for GST conjugation of TCE [53]: however, GST-alpha is not abundantly expressed in the placenta [33]. In addition to having a role in antioxidant response, GST is important for initiating glutathione-dependent metabolism of TCE [7].
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