Abstract
Cysteine conjugate β-lyases are enzymes which may be involved in the nephrotoxicity caused by a variety of S-cysteine conjugates which are formed from halogenated hydrocarbons.1 The enzymes catalyze the cleavage of S-cysteine conjugates to ammonia pyruvate and a thiol whose sulfur is derived from cysteine (eq. 1).2,3 The thiol containing cleavage fragments may be the species which are responsible for the nephrotoxicity of these compounds. This hypothesis is based on the observations of Schultze and coworkers who investigated the toxicity of S-1,2-dichlorovinyl-L-cysteine (DCVC)4–6. These workers found that DCVC was cleaved by mammalian and bacterial enzymes to pyruvate and ammonia, as well as an unidentified fragment which covalently bound to cellular macromolecules. However, there is no direct evidence linking the metabolism of S-cysteine conjugates and the toxicity of reactive electrophilic metabolites in vivo. In addition, it is not clear why the kidney is the target organ. We have investigated the properties of mammalian cysteine conjugate β-lyases in liver and kidney and developed a model culture system which responds to the toxic effects of a variety of S-cysteine conjugates. With these systems, we hope to establish a mechanism of toxicity for S-cysteine conjugates which are nephrotoxic.
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References
A.A. Elfarra and M.W. Anders, Renal processing of glutathione conjugates. Role in nephrotoxicity, Biochem. Pharmacol. 33: 3729 (1984).
W.B. Jakoby, J. Stevens, M.W. Duffel and R.A. Weisigar, The terminal enzymes of mercapturate formation and the thiomethyl shunt, Rev. Biochem. Toxicol. 6: 97 (1984).
J.J. Rafter, J. Bakke, G. Larsen, B. Gustafsson and J.-A. Gustafsson, Role of the intestinal microflora in the formation of sulfur containing conjugates of xenobiotics. Rev. Biochem. Toxicol. 5: 387 (1983).
P.M. Anderson and M.O., Schultze, Cleavage of S-(1,2-dichlorovinyl)-Lcysteine by an enzyme of bovine origin, Arch. Biochem. Biophys. 111: 593 (1965).
R.F. Derr and M.O. Schultze, The metabolism of 35S-(1,2-dichlorovinyl)L-cysteine in the rat, Biochem. Pharmacol. 12: 465 (1963).
R.K. Bhattacharya and M.O. Schultze, Arch. Biochem, Biophys. Properties of DNA treated with S-1,2-dichlorovinyl-L-cysteine and a lyase. 153: 105 (1972).
M. Tateishi and H. Shimizu, Cysteine conjugate 0-lyase, in “Enzymatic basis of detoxication,” W.B. Jakoby,ed., Academic Press, New York (1980).
F.V. Sepulveda and J.P. Pearson, Neutral amino acid transport in cultured kidney tubule cells, in, “Tissue Culture of Epithelial Cells,” Mary Taub, ed., Plenum Press, New York (1985).
L.L. McKinney, J.C. Picken, F.B. Weakley, A.C. Eldridge, R.E. Campbell, J.C. Cowen and H.E. Beister, Possible toxic factor of trichloroethylene extracted soybean meal, J. Am. Chem. Soc. 81: 909 (1959).
P.J. van Bladeren, W. Buys, D.D. Breimer and A. van der Gen, The synthesis of mercapturic acids and their esters. Eur. J. Med. Chem. 15: 495 (1980).
J.L. Stevens, Isolation and characterization of an enzyme with both cysteine conjugate g-lyase activity and kynureninase activity, J. Biol. Chem. 260: 7945 (1985).
J.L. Stevens and W.B. Jakoby, Cysteine conjugate g-lyase, Mol. Phramacol. 23: 761 (1983).
J.L. Stevens, Cysteine conjugate g-lyase in rat kidney cortex: Subcellular localization and relationship of the hepatic enzyme, Biochem. Biophys. Res. Comm. 129: 499 (1985).
E.W. Miles, Special aspects of transaminases, in “Transaminases,” P. Christen and D. Metzler eds., John Wiley and Sons, New York (1985).
C. Walsh, “Enzymatic reaction mechanisms,” W.H. Freeman and Co., San Fransisco (1979).
G.S. Bild and J.C. Morris, Detection of ß-carbanion formation during kynurenine hydrolysis catalyzed by Pseudomonas marginalis kynureninase, Arch. Biochem. Biophys. 235: 41 (1984).
G.M. Kishore, Mechanism-based inactivation of bacterial kynureninase by ß-substituted amino acids, J. Biol. Chem. 259: 10669 (1984).
H. Ueno and D. Metzler, Chemistry of the inactivation of cytosolic aspartate aminotransferase by serine 0-sulfate, Biochemistry, 21: 4387 (1982).
M.W. Anders, et al., this volume.
T. Beeler and J.E. Churchich, Reactivity of the phosphopyridoxal groups of cystathionase, J. Biol. Chem. 251: 5267 (1976).
C.A. Rabito and M.V. Karish, Polarized amino acid transport by an epithelial cell line of renal origin. J. Biol. Chem. 258, 2543 (1983).
B. Sacktor, Na+ gradient dependent transport systems in renal proximal tubule brush border membrane vesicles. In: Membranes and Transport, M. Taub, ed., Plenum Press, New York (1982).
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© 1986 Plenum Press, New York
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Stevens, J.L., Hayden, P., Taylor, G. (1986). Studies on the Mechanism of S-Cysteine Conjugate Metabolism and Toxicity in Rat Liver, Kidney, and a Cell Culture Model. In: Kocsis, J.J., Jollow, D.J., Witmer, C.M., Nelson, J.O., Snyder, R. (eds) Biological Reactive Intermediates III. Advances in Experimental Medicine and Biology, vol 197. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5134-4_36
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DOI: https://doi.org/10.1007/978-1-4684-5134-4_36
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