Abstract
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.
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References
J.A. Miller and E.C. Miller, The metabolic activation of carcinogenic aromatic amines and amides, Progr. Exp. Tumor Res. 11: 273 (1969).
A. Larsson, S. Orrenius, A. Holmgren, and B. Mannervik, eds., “Functions of Glutathione: Biochemical, Physiological, Toxicological and Clinical Aspects”, Raven Press, New York (1983).
J.R. Gillette, J.R. Mitchell, and B.B. Brodie, Biochemical basis for drug toxicity, Ann. Rev. Pharmacol. 14: 271 (1974).
J.R. Mitchell, D.J. Jollow, W.Z. Potter, J.R. Gillette, and B.B. Brodie, Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione, J. Pharmacol. Exp. Ther. 187: 211 (1973).
N.S. Kosower and E.M. Kosower, The glutathione status of cells, Int. Rev. Cytol. 54: 109 (1978).
A. Meister and M. Anderson, Glutathione, Ann. Rev. Biochem. 52: 711 (1983)
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).
W.B. Jakoby, The glutathione-S-transferases: a group of multifunctional detoxification proteins, Adv. Enzymol. 46: 383 (1978)
A. Wendel, Glutathione peroxidase, in: “Enzymatic Basis of Detoxication”, W.B. Jakoby, ed., Academic Press, New York (1980).
L. Eklöw, P. Moldéus, and S. Orrenius, Oxidation of glutathione during hydroperoxide metabolism. A study using isolated hepatocytes and the glutathione reductase inhibitor 1,3-bis(2-chloroethyl)-1nitrosourea, Eur. J. Biochem. 138: 459 (1984)
S.K. Srivastava and E. Beutler, The transport of oxidized glutathione from human erythrocytes, J. Biol. Chem. 244: 9 (1969).
T.P.M. Akerboom, M. Bilzer, and H. Sies, Competition between transport of glutathione disulfide (GSSG) and glutathione-S-conjugates from perfused rat liver into the bile, FEBS Lett. 140: 73 (1982).
P. Nicotera, M. Moore, G. Bellomo, F. Mirabelli, and S. Orrenius, Demonstration and partial characterization of glutathione disulfide-stimulated ATPase activity in the plasma membrane fraction from rat hepatocytes, J. Biol. Chem. 260: 1999 (1985).
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).
F.G. Hopkins, An autooxidable constituent of the cell, Biochem. J. 15: 296 (1921).
E. Lundsgaard, Biochem. Z. 217: 162 (1930).
D.J. Jollow, J.R. Mitchell, W.Z. Potter, D.C. Davis, J.R. Gillette, and B.B. Brodie, Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo, J. Pharmacol. Exp. Ther. 187: 195 (1973).
L. Ernster, DT-diaphorase, Meth. Enzymol. 10: 309 (1967).
H. Thor, M.T. Smith, P. Hartzell, G. Bellomo, S.A. Jewell, and S. Orrenius, The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes. A study of the implications of oxidative stress in intact cells, J. Biol. Chem. 257: 12419 (1982).
D. Di Monte, D. Ross, G. Bellomo, L. Eklöw, and S. Orrenius, Alterations in intracellular thiol homeostasis during the metabolism of menadione by isolated rat hepatocytes, Arch. Biochem. Biophys. 235: 334 (1984).
D. Di Monte, G. Bellomo, H. Thor, P. Nicotera, and S. Orrenius, Menadione-induced cytotoxicity is associated with protein thiol oxidation and alteration in intracellular Ca2+ homeostasis. Arch. Biochem. Biophys. 235: 343 (1984).
S.A. Jewell, G. Bellomo, H. Thor, S. Orrenius, and M.T. Smith, Bleb formation in hepatocytes during drug metabolism is caused by disturbances in thiol and calcium ion homeostasis, Science, 217: 1257 (1982).
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.
E. Carafoli and M. Crompton, The regulation of intracellular Ca2+, Curr. Top. Membr. Transp. 10: 151 (1978).
A.C. Lehninger, A. Vercesi, and E.P. Bababunmi, Regulation of Ca2+ release from mitochondria by the oxidation-reduction state of pyridine nucleotides, Proc. Natl. Acad. Sci. USA, 75: 1690 (1978).
A.E. Vercesi, Possible participation of membrane thiol groups on the mechanism of NAD(P)+-stimulated Ca2+ efflux from mitochondria, Biochem. Biophys. Res. Commun. 119: 305 (1984).
P. Goldstone and H. Crompton, Evidence for ß-adrenergic activation of Na+-dependent efflux of Ca2+ from isolated liver mitochondria, Biochem. J. 204: 369 (1982).
L. Moore, T. Chen, H.R. Knapp, and E.J. Landon, Energy dependent calcium sequestration activity in rat liver microsomes, J. Biol. Chem. 250: 4562 (1975).
P.B. Moore and N. Kraus-Friedman, Hepatic microsomal Ca2+-dependent ATPase, Biochem. J. 214: 69 (1983).
N. Kraus-Friedman, J. Biber, H. Murer, and E. Carafoli, Calcium uptake in isolated hepatic plasma membrane vesicles, Eur. J. Biochem. 129: 7 (1982).
H.J. Berridge and R.F. Irwin, Inositol trisphosphate, a novel second messenger in cellular signal transduction, Nature, London, 312: 315 (1984).
G. Bellomo, S.A. Jewell, and S. Orrenius, The metabolism of menadione impairs the ability of rat liver mitochondria to take up and retain calcium, J. Biol. Chem. 257: 11558 (1982)
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).
P. Nicotera, M. Moore, F. Mirabelli, G. Bellomo, and S. Orrenius, Inhibition of hepatocyte plasma membrane Ca2+-ATPase activity by menadione metabolism and its restoration by thiols, FEBS Lett. 181: 149 (1985).
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© 1986 Plenum Press, New York
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Nicotera, P., Orrenius, S. (1986). Role of Thiols in Protection Against Biological Reactive Intermediates. 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_4
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DOI: https://doi.org/10.1007/978-1-4684-5134-4_4
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