The Nephrotoxicity of 2,5-Dichloro-3-(Glutathion-S-YL)-1,4-Benzo-Quinone, and 2,5,6-Trichloro-3-(Glutathion-S-YL)-1,4-Benzoquinone is Potentiated by Ascorbic Acid and AT-125
We have previously shown that oxidation of either 2-bromohydroquinone (2-BrHQ) or hydroquinone (HQ) in the presence of glutathione (GSH) results in the formation of several isomeric and multi-substituted GSH conjugates. Administration of 2-Br-(diGSyl)HQ and 2,3,5-(tri-GSyl)HQ (10–30 μmol, i.v.) to male Sprague Dawley rats caused selective necrosis of renal proximal tubules (Monks et al., 1985, 1988; Lau et al., 1988). The tissue selectivity of these conjugates appears to be a consequence of their metabolism and selective accumulation by renal proximal tubular cells, mediated by γ-glutamyl transpeptidase (γ-GT). Pretreatment of animals with AT-125 (Acivicin; L-[aS-5S]-a-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, 10 mg/kg) an inhibitor of several glutamine (Weber, 1983) utilizing enzymes, including γ-GT (Monks et al., 1985) protected rats from both 2-Br-(diGSyl)HQ and 2,3,5-(triGSyl)HQ mediated nephrotoxicity (Monks et al., 1988; Lau et al., 1988). The cytotoxicity appears to be a consequence of oxidation of the corresponding cysteinylglycine(CYSGLY) and/or cysteine conjugates to their equivalent quinones. We have therefore investigated the toxicity of the GSH conjugates of 2,5-dichloro-1,4-benzoquinone (DCBQ) and 2,3,5-trichloro-1,4-benzoquinone (TCBQ). These compounds have certain similarities to the 2-BrHQ and HQ conjugates, the major difference being that reaction of the chloroquinones with GSH results in the formation of a conjugate that resides in the quinone form when reaction with GSH occurs at a chlorine-substituted carbon atom (Figure 1).
KeywordsBlood Urea Nitrogen Renal Proximal Tubule Selective Accumulation Tissue Selectivity Renal Proximal Tubular Cell
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- Lau, S.S., Hill, B.A., Highet, R.J., and Monks, T.J. (1988). Sequential oxidation and glutathione addition to 1,4-benzoquinone: Correlation of toxicity with increased glutathione substitution. Molec. Pharmacol. 34, 829–836.Google Scholar
- Mertens, J.J.W.M., Temmink, J.H.M., Van Bladeren, P.J., Lau, S.S. and Monks,T.J. (1990). Inhibition of g-glutamyl transpeptidase potentiates the nephrotoxicity of glutathione conjugated chlorohydroquinones. In preparation.Google Scholar
- Monks, T.J., Highet, R.J. and Lau, S.S. (1988). 2-Bromo-(diglutathion-Syl)hydroquinone nephrotoxicity: Physiological biochemical and electrochemical determinants. Moiec. Pharmacol. 34, 492–500.Google Scholar