Role of Thiols in Protection Against Biological Reactive Intermediates
Thanks to the pioneering work of Elizabeth and James Miller1 it is now well established that the cytotoxic and carcinogenic effects of a wide variety of chemicals are mediated by reactive products formed during their biotransformation in the organism. It is equally clear that there exist a number of protective systems which can trap, or inactivate, toxic metabolites and thereby prevent their accumulation within the tissues and subsequent toxic effects. Although phase I reactions, in particular those mediated by the cytochrome P-450-linked monooxygenase system, are most often responsible for the production of toxic metabolites, there are now many examples of metabolic activation via phase II reactions, despite the fact that the latter normally serve a protective function. Hence, it is obvious that the formation of toxic metabolites cannot be attributed to any single enzyme or enzyme system, and that the balance between metabolic activation and inactivation is absolutely critical in deciding whether exposure to a potentially toxic compound will result in toxicity, or not.
KeywordsRedox Cycling Pyridine Nucleotide Protein Thiol Plasma Membrane Fraction Glutathione Conjugate
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- 1.J.A. Miller and E.C. Miller, The metabolic activation of carcinogenic aromatic amines and amides, Progr. Exp. Tumor Res. 11: 273 (1969).Google Scholar
- 2.A. Larsson, S. Orrenius, A. Holmgren, and B. Mannervik, eds., “Functions of Glutathione: Biochemical, Physiological, Toxicological and Clinical Aspects”, Raven Press, New York (1983).Google Scholar
- 7.A. Meister, S.S. Tate, and L.L. Ross, Membrane bound γ-glutamyl trans-peptidase, in: “The Enzymes of Biological Membranes”, A. Martinosi, ed., Plenum Press, New York (1976).Google Scholar
- 9.A. Wendel, Glutathione peroxidase, in: “Enzymatic Basis of Detoxication”, W.B. Jakoby, ed., Academic Press, New York (1980).Google Scholar
- 14.P. Nicotera, C. Baldi, S.-A. Svensson, R. Larsson, G. Bellomo, and S. Orrenius, Glutathione-S-conjugates stimulate ATP hydrolysis in the plasma membrane fraction of rat hepatocytes, FEBS Lett. in press, (1985).Google Scholar
- 15.F.G. Hopkins, An autooxidable constituent of the cell, Biochem. J. 15: 296 (1921).Google Scholar
- 16.E. Lundsgaard, Biochem. Z. 217: 162 (1930).Google Scholar
- 23.F.C. Bygrave, Intracellular calcium and its regulation in liver, in: “Progress in Clinical and Biological Research”, F. Bronner and M. Peterlik, eds., A.R. Liss, New York.Google Scholar
- 33.H. Thor, P. Hartzell, S.-Åson, S. Orrenius, F. Mirabelli, V. Marinoni, and G. Bellomo, On the role of thiol groups in the inhibitor of liver microsomal Ca2+ sequestration by toxic agents, Biochem. Pharmac. in press (1985).Google Scholar