Glutathione S-conjugates

Intracellular thiolate ligands such as glutathione (GSH, the tripeptide y-L-Glu-L-Cys-Gly) are believed to inactivate cisplatin because the reactions with cisplatin tend to be irreversible (35). Elevated levels of GSH have been observed in cisplatin-resistant cells. Recently, it has been shown that an MRP gene, which encodes a human ATP-dependent glutathione S-conjugate export pump (GS-X pump), is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells (36). The GS-X pump may contribute to the excretion of Pt-GS complexes from cells (37). 

Jedlitschky, G., Leier, I., Buchholz, U., Center, M. and Keppler, D. (1994) ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Research, 54, 4833—4836. 

Ishikawa, T., Muller, M., Klunemann, C., Schaub, T. and Keppler, D. (1990) ATP-dependent primary active transport of cysteinyl leukotrienes across liver canalicular membrane. Role of the ATP-dependent transport system for glutathione S-conjugates. Journal of Biological Chemistry, 265, 19279-19286. 

Covalent protein adducts of quinones are formed through Mchael-type addihon reachon with protein sulfhydryl groups or glutathione. Metabolic activahon of several toxins (e.g., naphthalene, pentachlorophenol, and benzene) into quinones has been shown to result in protein quinone adducts (Lin et al, 1997 Rappaport et al, 1996 Zheng et al., 1997). Conversion of substituted hydroquinones such as p-aminophenol-hydroquinone and 2-bromo-hydroquinone to their respective glutathione S-conjugates must occur to allow bioactivation into nephrotoxic metabolites (Dekant, 1993). Western blot analysis of proteins from the kidneys of rats treated with 2-bromo-hydroquinone has revealed three distinct protein adducts conjugated to quinone-thioethers (Kleiner et al, 1998). 

Dekant, W., 1993, Bioactivation of nephrotoxins and renal carcinogens by glutathione S-conjugate formation. Toxicol. Lett. 67 151-160 Dooley, D.M., 1999, Stmcture and biogenesis oftopaquiones and related cofactors. J. Biol. Inorg. Chem. 4 1-11... 

Vamvakas S, Elfarra AA, Dekant W, et al. 1988. Mutagenicity of amino-acid and glutathion S-conjugates in the ames test. Mutat Res 206 83-90. 

Lu, Y.-P. et al., AtMRP2, an Arabidopsis ATP binding cassette transporter able to transport glutathione S-conjugates and chlorophyll catabolites functional comparisons with AtMRPl. Plant Cell, 10, 267, 1998. 

Lu Y-P, Li Z-S, Rea PA. 1997. AtMRPl gene of Arabidopsis encodes a glutathione S-conjugate pump Isolation and functional definition of a plant ATP-binding cassette transporter gene. Proc Natl Acad Sci USA 94 8243-8248. 

Martinoia E, Grill E, Tommasini R, Kreuz K, Amrhein N. 1993. An ATP-dependent glutathione S-conjugate export pump in the vacuolar membrane of plants. Nature 364 247-249. 

Saha, N Stoll, B., Lang, F., Haussinger, D. (1992). Effect of anisotonic cell volume modulation on glutathione-S-conjugate release, t-butylhydroperoxide metabolism and the pentose-phosphate shunt in perfused rat liver. Eur. J. Biochem. 209, 437-444. 

Commanndeur JNM, Stintjes GJ, Vermeulen NPE (1995) Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Pharmacol Rev 47 271-330... 

Li, Z.-S., Zhao, Y. and Rea, RA. (1995) Magnesium adenosine 5 -triphosphate-energized transport of glutathione-S-conjugates by plant vacuolar membrane vesicles. Plant Physiol, 107,1257-68. 

Muller M, de Vries EGE, Jansen PLM. Role of multidrug resistance protein (MRP) in glutathione S-conjugate transport in mammalian cells. J Hepatol 1996 24(suppl 1) 10(V8. 

Figure 2, Activation of glutathione-conjugates to reactive thiols. Halogenated alkenes form glutathione-S-conjugates and are metabolized to nephrotoxins via this pathway. This pathway results in the production of unstable reactive thiols, which are toxic. TheX represents the alkene.

Dekant W, Vamvakas S, and Anders MW. Formation and fate of nephrotoxic and cytotoxic glutathione S-conjugates cysteine conjugate beta-lyase pathway. Advances in pharmacology (San Diego, Calif) 27 115-162,1994. 

Dekant W. Chemical-induced nephrotoxicity mediated by glutathione S-conjugate formation. Toxicol Lett. 2001 124(l-3) 21-36. 

Ishikawa, T. The ATP-dependent glutathione S-conjugate export pump. Trends Biochem. Sci. 17 463 -468, 1992. 

Thiele, D.J., and Rea, P.A. (1996) The yeast cadmium factor protein (Ycflp) is a vacuolar glutathione S-conjugate pump. The Journal of Biological Chemistry, 271. 6509-6517. 

Akerboom TPM, BUzer M, Sies H (1982b) Competition between transport of glutathione disulfide (GSSG) and glutathione-S-conjugates from perfused rat liver into bUe. FEBS Lett 140 73... 

Kondo T, Murao M, Taniguchi N (1982) Glutathione S-conjugate transport using inside-out vesicles from human erythrocytes. Eur J Biochem 125 551 Lu SC, Kuhlenkamp J, Ge JL, Sun WM, Kaplowitz N (1994) Specificity and directionality of thiol effects on sinusoidal glutathione transport in rat liver. Mol Pharmacol 46 578-85... 

Formation and Fate of Nephrotoxic and Cytotoxic Glutathione S-Conjugates Cysteine Conjugates Cysteine Conjugate b-Lyase Pathway... 

YCFl) is a vacuolar glutathione S-conjugate pump. J Biol Chem 271 6509-6517, 1996. 

Perek N, Prevot N, Koumanov F, Frere D, Sabido O, Beauchesne P et al. Involvement of the glutathione S-conjugate compounds and the MRP protein in Tc-99m-tetrofosmin and Tc-99m-sestamibi uptake in glioma cell lines. Nucl Med Biol 2000 27 299-207. 

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