The Role of γ-Glutamyl Transpeptidase in Hydroquinone-Glutathione Conjugate Mediated Nephrotoxicity
We have previously shown that oxidation of 2-bromohydroquinone (2-BrHQ) in the presence of glutathione (GSH) gives rise to a mixture of mono- and di-substituted GSH conjugates. Administration of the di-substituted conjugates to rats (30 μmol/kg, intravenously) caused extensive necrosis of renal proximal tubular cells, while the three mono-substituted GSH conjugates exhibited significantly less toxicity (Monks, et al., 1985, 1988). We subsequently investigated the toxicological properties of the products formed by the interaction of GSH with 1,4-benzoquinone (BQ). The chemical reaction of BQ with GSH resulted in the formation of GSH adducts that exhibited increasing degrees of GSH substitution (Lau, et al., 1988). Administration of these conjugates (50 μmol/kg, i.v.) to male Sprague-Dawley rats caused varying degrees of renal proximal tubular necrosis (Table 1). 2,3,5-(tri-GSyl)HQ was the most potent nephrotoxicant, demonstrating a 10 fold elevation in blood urea nitrogen (BUN) as compared to control animals. 2,3-, 2,5- and 2,6-(di-GSyl)HQ exhibited similar degrees of nephrotoxicity, eliciting an approximately 3 fold elevation in BUN over control levels. 2-(GSyl)HQ and 2,3,5,6-(tetra-GSyl)HQ were not toxic at the 50 μmol/kg dose (Table 1). However, 2-(GSy1)HQ produced signs of toxicity at a dose of 250 μmol/kg (BUN = 43.6 ± 4.3). None of these conjugates caused any elevations in serum pyruvate glutamate transaminase (SGPT) (Table 1) or histological alterations in the liver, suggesting that quinol-GSH conjugates may be selective nephrotoxicants.
KeywordsHydrolysis Toxicity HPLC Urea Glutathione
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