Mechanisms for the Generation of Oxygen Radicals by Drugs

  • Daniel M. Ziegler
Part of the Basic Life Sciences book series (BLSC, volume 49)


In this report I will give a brief overview of drug-dependent metabolic reactions that can generate reactive oxygen species in tissues. The term drug is used here in its widest sense and includes any physiologically useless compound, either synthetic or naturally occurring, that can transfer one or two electrons to dioxygen via enzyme-catalyzed reactions. At the molecular level it is an enzyme that recognizes a specific structure and sustains the reaction. Therefore, a discussion of biochemical mechanisms is primarily concerned with the nature of the reaction and the identity of enzymes that catalyze reactions. The following review follows this general plan and focuses on enzymes that catalyze oxidation or reduction of functional groups in xenobiotics that often lead to the generation of oxygen radicals.


Xanthine Oxidase Monoamine Oxidase Nicotinamide Adenine Dinucleotide Phosphate Aldehyde Oxidase Aromatic Nitro Compound 
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  1. 1.
    R.M. Denny, R.R. Fritz, N.T. Patel, and C.W. Abell, Human liver MAO-A and MAO-B separated by immunoaffinity, Science 215:1400–1403 (1982).CrossRefGoogle Scholar
  2. 2.
    L.M. Kochersperger, A. Waguespack, J.C. Patterson, L.C. Hsieh, W. Weyler, J.I. Salach, and R.M. Denny, Immunological uniqueness of human monoamine oxidases A and B: New evidence from studies with monoclonal antibodies to human monoamine oxidase A, J. Neurosci. 5:2874–2881 (1985).PubMedGoogle Scholar
  3. 3.
    K.F. Tipton, Monoamine Oxidase, in: “Handbook of Physiology,” H. Blaschko and A.D. Smith, eds., American Physiological Society, Washington D.C. (1975).Google Scholar
  4. 4.
    M.W. Coomes and R.A. Prough, The mitochondrial metabolism of 1,2-disubstituted hydrazines, procarbazine and 1,2-dimethylhydrazine, Drug Metab. Dispos. 11:550–555 (1983).PubMedGoogle Scholar
  5. 5.
    J.I. Salach, T.P. Singer, N. Castagnoli, and A.J. Trevor, Oxidation of the neurotoxic amine l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by monoamine oxidases A and B and suicide inactivation of the enzymes by MPTP, Biochem. Biophys. Res. Comm. 125:831–835 (1984).PubMedCrossRefGoogle Scholar
  6. 6.
    R.B. Silverman, C.K. Hiebert, and M.L. Vagquez, Inactivation of monoamine oxidase by allylamine does not result in flavin attachment, J. Biol. Chem. 260:14648–14652 (1985).PubMedGoogle Scholar
  7. 7.
    K.V. Rajagopalan, Xanthine oxidase and aldehyde oxidase, in: “Enymatic Basis of Detoxication” Vol. 1, W.B. Jakoby ed., Academic Press, New York, New York (1980).Google Scholar
  8. 8.
    T.A. Krenitsky, M.N. Shannon, G.B. Elion, and G.H. Hitchings, A comparison of the specificities of xanthine oxidase and aldehyde oxidase, Arch. Biochem. Biophys. 150:585–599 (1972).PubMedCrossRefGoogle Scholar
  9. 9.
    D.G. Johns, A.T. Jannotti, A.C. Sartorelli, B.A. Booth, and J.R. Bertino, The identity of rabbit liver methotrexate oxidase, Biochem. Biophys. Acta 105:380–382 (1965).PubMedCrossRefGoogle Scholar
  10. 10.
    K.F. McLane, J. Fisher, and Ramakrishnan, Reductive drug metabolism, Drug Meta. Revs. 14:741–799 (1983).CrossRefGoogle Scholar
  11. 11.
    H.M. Hassan and L. Fridovich, Intracellular production of superoxide radical and of hydrogen peroxide by redox active compounds, Arch. Biochem. Biophys. 196:385–395 (1979).PubMedCrossRefGoogle Scholar
  12. 12.
    H. Thor, M.T. Smith, P. Hartzell, G. Bellomo, S.A. Jewell, and S. Orrenius, The metabolism of menadione (2-Methyl-l,4-Napthoquinone) by isolated hepatocytes: A study of the implications of oxidative stress in intact cells, J. Biol. Chem. 257:12419–12425 (1982).PubMedGoogle Scholar
  13. 13.
    W. Thayer, Adriamycin stimulates superoxide formation in submitochondrial particles, Chem. Biol. Interact. 19:265–278 (1977).PubMedCrossRefGoogle Scholar
  14. 14.
    J.H. Doroshow and J. Reeves, Daunorubicin-stimulated reactive oxygen metabolism in cardiac sacrosomes, Biochem. Pharmacol. 30:259–262 (1981).PubMedCrossRefGoogle Scholar
  15. 15.
    N. Yamoaka, T. Kato, K. Nishida, S. Shimizu, M. Fukushima, and K. Ota, Increase of antitumor effect of bleomycin by reduced nicotinamide adenine dinucleotide phosphate and microsomes in vitro and in vivo, Cancer Res. 40:2051–2053 (1980).Google Scholar
  16. 16.
    M. Tomasz and R. Lipman, Reductive metabolism and alkylating activity of mitomycin c induced by rat liver microsomes, Biochemistry. 20:5056–5061 (1981).PubMedCrossRefGoogle Scholar
  17. 17.
    D. DiMonte, G. Bellomo, H. Thor, P. Nicotera, and S. Orrenius, Menadione-induced cytotoxicity is associated with protein thiol Oxidation and alteration in intracellular Ca++ homeostasis, Arch. Biochem. Biophys. 235:343–350 (1984).CrossRefGoogle Scholar
  18. 18.
    S. Orrenius, H. Thor, and D. DiMonte, Mechanisms and implications of oxidative stress studied with intact cells, in: “Oxidative Damage and Related Enzymes,” G. Rolillo and J.V. Bannister eds., Harwood Academic Publishers, London and New York (1987).Google Scholar
  19. 19.
    B.S.S. Masters, Bilimoria, H. Kamin, and Q.H. Gibson, The mechanism of 1- and 2-electron transfers catalyzed by reduced triphosphopyridine nucleotide-cytochrome c reductase, J. Biol. Chem. 240:408 1–4088 (1965).Google Scholar
  20. 20.
    J.W. Patterson, A. Lazarow, and S. Levey, Reactions of alloxan and dialuric acid with the sulfhydryl group, J. Biol. Chem. 177:197–204 (1949).PubMedGoogle Scholar
  21. 21.
    A. Holmgren and C. Lyckeborg, Enzymatic reduction of alloxan by thioredoxin and NADPH-thioredoxin reductase, Proc. Natl. Acad. Sci. USA 77:5149–5152 (1980)PubMedCrossRefGoogle Scholar
  22. 22.
    R.J. Burk, R.A. Lawrence, and J.M. Lave, Liver necrosis and lipid preroxidation in the rat as a result of paraquat and diquat administration, J. Clin. Invest. 65:1024–1031 (1980).PubMedCrossRefGoogle Scholar
  23. 23.
    C.V. Smith, H. Hughes, B.H. Lauterburg, and J.R. Mitchell, Oxidant stress and hepatic necrosis in rats treated with diquat, J. Pharmacol. Exp. Ther. 235:172–177 (1985).PubMedGoogle Scholar
  24. 24.
    R.L. Keeling, L.L. Smith, and W.N. Aldridge, The formation of mixed disulfides in rat lung following paraquat administration, Biochem. Biophys. Acta 716:249–257 (1982).PubMedCrossRefGoogle Scholar
  25. 25.
    J.C. Gage, The action of paraquat and diquat on the respiration of liver cell fractions, Biochem. J. 109:757–767 (1968).PubMedGoogle Scholar
  26. 26.
    R.C. Baldwin, A. Pasi, J.T. MacGregor, and C.H. Hine, Rates of radical formation from the dipyridylium herbicides paraquat, diquat, and morfamquat in homogenates of rat lung, kidney, and liver, inhibitory effect of carbon monoxide, Toxicol. Appl. Pharmac. 32:298–304 (1975).CrossRefGoogle Scholar
  27. 27.
    R.P. Mason and J.L. Holtzman, The role of catalytic superoxide formation in the O2 inhibition of nitroreductase, Biochem. Biophys. Res. Comm. 67:1267–1274 (1975).PubMedCrossRefGoogle Scholar
  28. 28.
    D.S. Hewick, Reductive metabolism of nitrogen-containing functional groups, In: “Metabolic Basis of Detoxication,” W.B. Jakoby, J.R. Bend and J. Caldwell eds., Academic Press, New York, New York (1982).Google Scholar
  29. 29.
    P. Eyer, Reactions of nitroarenes with sulfhydryl groups: Reaction mechanism and biological significance, in: “Biological Oxidation of Nitrogen in Organic Molecules,” J.W. Gorrod and L.A. Damani eds., Ellis Horwood, Chichester (1985).Google Scholar
  30. 30.
    R.P. Mason, F.J. Peterson, and J.L. Holtzman, Inhibition of azoreductase by oxygen, Mol. Pharmacol. 14:665–671 (1978).PubMedGoogle Scholar
  31. 31.
    G. Holder, H. Yagi, P. Dansette, D.M. Jerina, W. Levin, A.Y.H. Lu, and A.H. Conney, Effects of inducers and epoxide hydrase on the metabolism of benzo[a]pyrene by liver microsomes and a reconstituted system: Analysis by high pressure liquid chromatography, Proc. Nat. Acad. Sci. USA 7 1:4356–4360 (1974).CrossRefGoogle Scholar
  32. 32.
    S.W. Cummings and R.A. Prough, Butylated hydroxyanisole-stimulated NADPH oxidase activity in rat liver microsomal fractions, J. Biol. Chem. 258:12315–12319 (1983).PubMedGoogle Scholar
  33. 33.
    A.G. Hildebrandt and Roots, Reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent formation and breakdown of hydrogen peroxide during mixed function oxidation reactions in liver microsomes, Arch. Biochem. Biophys 171:385–397 (1975).CrossRefGoogle Scholar
  34. 34.
    H. Sies, A. Wahllander, and C. Waydas, Properties of glutathione disulfide (GSSG) and glutathione-S-conjugate release from perfused rat liver, in: “Functions of Glutathione in Liver and Kidney” H. Sies and A. Wendel eds., Springer, Berlin (1978).Google Scholar
  35. 35.
    D.P. Jones, L. Eklow, H. Thor, and S. Orrenius, Metabolism of hydrogen peroxide in isolated hepatocytes: Relative contribution of catalase and glutathione peroxidase in decomposition of endogenous generated H2O2, Arch. Biochem. Biophys. 210:505–516 (1981).PubMedCrossRefGoogle Scholar
  36. 36.
    P.A. Krieter, D.M. Ziegler, K.E. Hill, and R.F. Burk, Studies on the biliary efflux of GSH from rat liver due to metabolism of aminopyrine, Biochem. Pharmacol. 34:955–960 (1985).PubMedCrossRefGoogle Scholar
  37. 37.
    P.A. Krieter, D.M. Ziegler, K.E. Hill, and R.F. Burk, Increased biliary GSSG efflux from rat livers perfused with thiocarbamide substrates for the flavin-containing monooxygenage, Mol. Pharmacol. 26:122–127 (1984).PubMedGoogle Scholar
  38. 38.
    D.M. Ziegler, Microsomal flavin-containing monooxygenase: Oxygenation of nucleophilic nitrogen and sulfur compounds, in: “Enzymatic Basis of Detoxication,” W.B. Jakoby ed., Academic Press, New York (1980).Google Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Daniel M. Ziegler
    • 1
  1. 1.Clayton Foundation Biochemical Institute and Department of ChemistryThe University of Texas at AustinAustinUSA

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