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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

  • Terrence J. Monks
  • Serrine S. Lau
  • Jos. J. W. Mertens
  • Johan H. M. Temmink
  • Peter J. van Bladeren
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 283)

Abstract

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).

Keywords

Blood Urea Nitrogen Renal Proximal Tubule Selective Accumulation Tissue Selectivity Renal Proximal Tubular Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 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
  2. 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
  3. Monks, T.J., Lau, S.S., Highet, R.J. and Gillette, J.R. (1985). Glutathione conjugates of 2-bromohydroquinone are nephrotoxic. Drug Metab. Dispos. 13, 553–559.PubMedGoogle Scholar
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Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Terrence J. Monks
    • 1
    • 2
  • Serrine S. Lau
    • 1
    • 2
  • Jos. J. W. Mertens
    • 2
  • Johan H. M. Temmink
    • 2
  • Peter J. van Bladeren
    • 2
  1. 1.Division of Pharmacology and Toxicology College of PharmacyThe University of Texas at AustinAustinUSA
  2. 2.Department of ToxicologyAgricultural UniversityWageningenThe Netherlands

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