S-Conjugate-dependent Toxicity: Alternatives to Animal Studies

M. W. Anders
Department of Pharmacology and Physiology, University of Rochester Medical Center,
601 Elmwood Avenue, Box 711, Rochester, New York 14642, U.S.A.

Correspondence: Professor M. W. Anders
Department of Pharmacology and Physiology, University of Rochester Medical Center,
601 Elmwood Avenue, Box 711, Rochester, New York 14642, U.S.A.
telephone: 716-275-1681; fax: 716-244-9283;
e-mail: mw_anders@urmc.rochester.edu

Presented at the 13th Annual Meeting of the Japanese Society for Alternatives to Animal Experiments. 13-14 November 1999, Tokyo, Japan.

Special Article

AATEX 7(1):37-46,2000
Abstract
Studies on the mechanisms of glutathione S-conjugate-dependent toxicity are a major focus of the research in our laboratory. These studies aim to elucidate the mechanism of the selective nephrotoxicity of a range of halogenated olefins or haloalkenes that undergo conversion to toxic metabolites by the cysteine conjugate b-lyase pathway. The b-lyase pathway is a multiorgan, multistep pathway that involves glutathione transferase-catalyzed glutathione S-conjugate formation in the liver, enzyme-catalyzed hydrolysis of the glutathione S-conjugates to the corresponding cysteine S-conjugates, active uptake of the S-conjugates by the kidney, and bioactivation by renal cysteine conjugate b-lyase. Although animal experiments are conducted to determine the nephrotoxicity of haloalkenes, a range of alternatives to the use of intact animals has also been employed in these studies. These alternatives include studies with purified and expressed enzymes, isolated rat and human hepatocytes, isolated rat renal proximal tubular cells, tissue culture, chemical models, Fourier-transform ion cyclotron resonance mass spectrometry, and computational chemistry. The use of the alternatives has allowed a reduction in the number of animals used and, in some cases, replacement of animals with in vitro models.


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