The Effects of Cytochrome P450 Inhibition On Glutathione Conjugation of Perchloroethylene and Trichloroethylene in Rat Renal Cortical Cells and Hepatocytes
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Authors
Hueni, Sarah
Issue Date
1998
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
Trichloroethylene (TRI) and Perchloroethylene (PER) are environmental
contaminants whose ingestion, inhalation or absorption can lead to species-, strain-, and
gender-specific toxicity and carcinogenicity through bioactivation, occurring by either
glutathione (GSH) conjugation or cytochrome P450 oxidation. Cytochrome P450
oxidation is thought to affect the lung, liver, and other extra-renal tissue, whereas GSH
conjugation is thought to lead to nephrotoxicity and nephrocarcinogenicity, through still
undetermined mechanisms. To better characterize their metabolism, the effects of
cytochrome P450 inhibitors on GSH conjugation ofTRI and PER in freshly isolated rat
renal cortical cells and hepatocytes were studied.
, Suspensions of cells were incubated with either TRI or PER and one of three
,
cytochrome P450 inhibitors: SKF 525A, metyrapone, or diethyldithiocarbamic acid
(DITC). These incubations were arrested at 15 min intervals with 70% perchloric acid
and reactive GSH conjugation metabolites of TRI and PER, S- (1,2-
dichlorovinyl)glutathione (DCVG) and S- (1,2,2-trichlorovinyl)glutathione (TCVG)
respectively, were measured by high-performance liquid chromatography. Amounts of
DCVG/TCVG were thought to be indicative of the amounts of TRIlPER metabolized by
the GSH conjugation pathway; however, these experiments were inconclusive.
Another set of experiments measured cell death in cell suspensions incubated with
PER and either diethyl maleate or buthionine sulfoximine (BSO) (inhibitors of the GSH
conjugation pathway) by % release of lactate dehydrogenase (LDH). Spectrophotometry
was used to determine cell death at 1 hour intervals, with inconclusive results.
Description
vi, 33 p.
Citation
Publisher
Kalamazoo College
License
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