Skip to main content
SpringerLink
Log in

Free radical intermediates and liver cell necrosis

  • Chapter
IUPHAR 9th International Congress of Pharmacology

Abstract

It is now well established that differences in the severity and incidence of tissue damage caused by foreign compounds frequently correlate with differences in the covalent binding of chemically reactive metabolites of the foreign compounds with various intracellular components (Snyder et al, 1982). Although such correlations suggest that the toxicities are caused by chemically reactive metabolites, they usually do not by themselves provide direct proof for the identity of the toxic metabolites nor the sequence of events that results in the manifestation of the tissue damage. Indeed, they simply imply that the covalently bound material and the toxic metabolites are derived from common intermediates (Gillette, 1974a,b).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • AHR, HJ., KING, L.J., NASTAINCZYK, W. & ULLRICH, V. (1980). The mechanism of chloroform and carbon monoxide formation from carbon tetrachloride by microsomal cytochrome P-450. Biochem. Pharmac., 29, 2855–2861.

    Article  Google Scholar 

  • BELLOMO, G., THOR, H. & ORRENIUS, S. (1984). Increase in cytosolic Ca++ concentration during t-butyl hydroperoxide metabolism by isolated hepatocytes involves NADPH oxidation and mobilization of intracellular Ca++ stores. FEBS Lett., 168, 38–42.

    Article  Google Scholar 

  • BUS, J.S. & GIBSON, J.E. (1984). Role of activated oxygen in chemical toxicity. In Drug Metabolism and Drug Toxicity. Mitchell, J.R. & Horning, M.G. (eds) pp. 21–32, New York: Raven Press.

    Google Scholar 

  • CAPDEVILA, J., CHACOS, N., WERRINGLOER, J., PROUGH, R. & ESTABROOK, R.W. (1982). Liver microsomal cytochrome P-450 and the oxidative metabolism of arachidonic acid. Proc natn. Acad. Sei. U.S.A., 78, 5362–5366.

    Article  Google Scholar 

  • DAHLIN, D.C., MIWA, G.T., LU, A.Y.H. & NELSON, S.D. (1984). N-acetyl-p-benzoquinone imine: A cytochrome P-450 mediated oxidation product of acetaminophen. Proc. natn. Acad. Sei. U.S.A., 81, 1327–1331.

    Article  Google Scholar 

  • DE MATTEIS, F., GIBBS, A.N., CANTONI, L. & FRANCIS, J. (1980). Substrate-dependent irreversible inactivation of cytochrome P-450: conversion of its haem moiety into modified porphyrins. In Environmental Chemicals, Enzyme Function and Human Disease. Evered, D. & Lawrenson, G. (eds) pp. 119–139. Ciba Foundation Symposium 76 (new series).

    Google Scholar 

  • DE MATTEIS, F., GIBBS, A.H. & UNSELD, A.P. (1982). Conversion of liver haem into N-substituted porphyrins or green products. In Biological reactive metabolites II. Snyder et al. (ed.) pp. 1319–1334, New York: Plenum Press.

    Google Scholar 

  • DE VRIES, J. (1981). Hepatotoxic metabolic activation of paracetamol and its derivatives phenacetin and benorilate: Oxygenation or electron transfer. Biochem. Pharmac, 30, 399–402.

    Article  Google Scholar 

  • EKLOW, L., MOLDEUS, P. & ORRENIUS, S. (1984). Oxidation of glutathione during hydroperoxide metabolism: A study using isolated hepatocytes and glutathione reductase inhibitor l,3-bis(2-chloroethyl)-l-nitroso urea. Eur. J. Biochem., 138, 459–463.

    Article  Google Scholar 

  • FRIDOVITCH, I. (1983). Superoxide radical: An endogenous toxicant. Ann. Rev. Pharmac. Toxic, 23, 239–257.

    Article  Google Scholar 

  • GERBER, J.G., MACDONALD, J.S., HARBISON, R.D., VILLENUE, J.-P., WOOD, A.J.J. & NIES, A.S. (1977). Effect of N-acetyl cysteine on hepatic covalent binding of paracetamol (acetaminophen) Lancet, i, 657–658.

    Article  Google Scholar 

  • GILLETTE, J.R. (1974a). A perspective on the role of chemically reactive metabolites of foreign compounds in toxicity: I. Correlation of changes in covalent binding of reactive metabolites with changes in the incidence and severity of toxicity. Biochem. Pharmac, 23, 2785–2794.

    Article  Google Scholar 

  • GILLETTE, J.R. (1974b). A perspective on the role of chemically reactive metabolites of foreign compounds in toxicity: II. Alterations in the kinetics of covalent binding. Biochem. Pharmac, 23, 2927–2938.

    Article  Google Scholar 

  • GILLETTE, J.R., BRODIE, B.B. & LADU, B.N. (1957). The oxidation of drugs by liver microsomes: On the role of TPNH and oxygen. J. Pharmac. exp. Ther., 119, 532–540.

    Google Scholar 

  • GILLETTE, J.R., LAU, S. & MONKS, T.J. (1984). Intra- and extra-cellular formation of metabolites from chemically reactive species. Biochem. Soc. Trans. 12, 4–7.

    Article  Google Scholar 

  • GILLETTE, J.R., NELSON, S.D., MULDER, G.J., JOLLOW, D.J., MITCHELL, J.R., POHL, L.R. & HINSON, J.A. (1982). Formation of chemically reactive metabolites of phenacetin and acetaminophen. In Biological Reactive Intermediates II. Snyder, R., Parke, D.V., Kocsis, J.J., Jollow, D.J., Gibson, CG. & Witmer, CM., (eds) pp. 931–950, New York: Plenum Publishing Co.

    Google Scholar 

  • GROVES, J.T., MCCLUSKY, G.A., WHITE, R.E. & COON, M.J. (1978). Aliphatic hydroxylation by highly purified liver microsomal cytochrome P-450. Evidence for a carbon radical. Biochem. Biophys. Res. Commun., 81, 154–160.

    Article  Google Scholar 

  • GUENGERICH, F.P. & MACDONALD. (1984). Chemical mechanisms of catalysis by cytochromes P-450: A unified view. Ace. Chem. Res., 17, 9–16.

    Article  Google Scholar 

  • HINSON, J.A., POHL, L.R. & GILLETTE, J.R. (1979). N-Hydroxyacetaminophen: A microsomal metabolite of N-hydroxyphenacetin but apparently not of acetaminophen. Life Sei., 24, 2133–2138.

    Article  Google Scholar 

  • HINSON, J.A., POHL, L.R., MONKS, TJ. & GILLETTE, J.R. (1981). Acetaminophen-induced hepatotoxicity. Life Sei., 29, 107–116.

    Article  Google Scholar 

  • JOLLOW, D.J., MITCHELL, J.R., POTTER, W.Z., DAVIS, D.C., GILLETTE, J.R. & BRODIE, B.B. (1973). Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J. Pharmac. exper. Ther., 187, 195–202.

    Google Scholar 

  • JONES, D.P., EKLOW, L., THOR, H. & ORRENIUS, S. (1981). Metabolism of hydrogen peroxide in isolated hepatocytes. Relative contributions of catalase and glutathione peroxidase in decomposition of en-dogenously generated H202. Archs. Biochem. Biophys., 210, 505–516.

    Article  Google Scholar 

  • KUBIC, V.L. & ANDERS, M.W. (1981). Mechanism of the microsomal reduction of carbon tetrachloride and halothan. Chem. Biol. Interactions, 34, 201–207.

    Article  Google Scholar 

  • LAU, S.S., MONKS, T.J. & GILLETTE, J.R. (1984a). Multiple reactive metabolites derived from bromobenzene. Drug Metab. Dispos., 12, 291–296.

    Google Scholar 

  • LAU, S.S., MONKS, T.C. & GILLETTE, J.R. (1984b). Identification of 2-bromohydro-quinone as a metabolite of bromobenzene: Implications for bromobenzene induced nephrotoxicity. J. Pharmac. exp. Ther. (inpress).

    Google Scholar 

  • LAU, S.S., MONKS, T.C, GREENE, K.E. & GILLETTE, J.R. (1984c). The role of ortho-bromophenol in the nephrotoxicity of bromobenzene in rats. Tox. Appl. Pharmac, 72, 539–549.

    Article  Google Scholar 

  • MASON, R.P. & HOLTZMAN, J.L. (1975). Role of catalytic superoxide formation in the oxygen inhibition of nitroreductase. Biochem. biophys. Res. Commun., 67, 1267–1274.

    Article  Google Scholar 

  • MASTERS, B.S.S., PROUGH, R.A. & KAMIM, H. (1975). Properties of the stable aerobic and anaerobic half-reduced states of NADPH-cytochrome creductase. Biochemistry, 14, 607–613.

    Article  Google Scholar 

  • MCCORD, J.M. & FRIDOVICH, I. (1968). The reduction of cytochrome c by milk xanthine oxidase. J. biol. Chem., 243, 5753–5760.

    Google Scholar 

  • MICO, B.A. & POHL, L.R. (1982). Reductive oxygenation of carbon tetrachloride: Trichloromethylperoxyl radical as a possible intermediate in the conversion of carbon tetrachloride to electrophilic chlorine. Archs. Biochem. Biophys., 225, 596–609.

    Article  Google Scholar 

  • MICO, B.A., BRANCHFLOWER, R.W. & POHL, L.R. (1983). Formation of electrophilic chlorine from carbon tetrachloride: Involvement of cytochrome P-450. Biochem. Pharmac, 32, 2357–2360.

    Article  Google Scholar 

  • MITCHELL, J.R., JOLLOW, D.J., POTTER, W.Z., DAVIS, D.C., GILLETTE, J.R. & BRODIE, B.B. (1973a). Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J. Pharmac. exp. Ther., 187, 185–194.

    Google Scholar 

  • MITCHELL, J.R., JOLLOW, D.J., POTTER, W.Z., GILLETTE, J.R. & BRODIE, B.B. (1973b). Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmac. exp. Ther., 187, 211–217.

    Google Scholar 

  • MITCHELL, J.R., SMOTH, C.V., LAUTERBURG, B.H., HUGHES, H., CORCORAN, G.B. & HORNING, E.C. (1984). Reactive metabolites and the pathophysiology of acute lethal cell injury. In Drug metabolism and Drug Toxicity. Mitchell, J.R. & Horning, M.G. (eds) pp. 301–319, New York: Raven Press.

    Google Scholar 

  • MONKS, T.J., HINSON, J.A. & GILLETTE, J.R. (1982). Bromobenzene and p-bromophenol toxicity and covalent binding in vivo. Life Sei., 30, 841–848.

    Article  Google Scholar 

  • MONKS, T.J., LAU, S. & GILLETTE, J.R. (1984). Diffusion of reactive metabolites out of hepatocytes: studies with bromobenzene. J. Pharmac. exp. Ther., 228, 393–399.

    Google Scholar 

  • NELSON, S.D., DAHLIN, D.C, RAUCKMAN, E.J. & ROSEN, G.M. (1981). Peroxidase-mediated formation of reactive metabolites of acetaminophen. Mol. Pharmac, 20, 195–199.

    Google Scholar 

  • NELSON, S.D., FORTE, A.J. & DAHLIN, D.C. (1980). Lack of evidence of N-hydroxy-acetaminophen as a reactive metabolite of acetaminophen in vitro. Biochem. Pharmac, 29, 1617–1620.

    Article  Google Scholar 

  • NELSON, S.D., MITCHELL, J.R., DYBING, E. & SASAME, H.A. (1976). Cytochrome P-450 mediated oxidation of 2-hydroxyestrogens to reactive intermediates. Biochem. biophys. Res. Commun., 70, 1157–1165.

    Article  Google Scholar 

  • OPRIAN, D.D. & COON, M.J. (1982). Reactions of oxygenated Plm In Microsomes, Drug Oxidations and Drug Toxicity. Sato, R. & Kato, R. (eds) pp. 139–145, New York: Wiley-Interscience.

    Google Scholar 

  • ORTIZ DE MONTELLANO, P.R. (1984). Alkenes and alkynes. In Bioactivation of Foreign Compounds. Anders, M.W. (ed.) New York: Academic Press, (in press).

    Google Scholar 

  • ORTIZ DE MONTELLANO, P.R. & CORREIA, M.A. (1983). Suicidal destruction of cytochrome P-450 during oxidative drug metabolism. Ann. Rev. Pharmac. Toxic, 23, 481–503.

    Article  Google Scholar 

  • POHL, L.R. & GEORGE, J.W. (1983). Identification of dich-loromethyl carbene as a metabolite of carbon tetrachloride. Biochem. biophys. Res. Commun., 117, 367–371.

    Article  Google Scholar 

  • POHL, L.R. & KRISHNA, G. (1978). Deuterium isotope effect in bioactivation and hepatotoxicity of chloroform. Life Sei., 23, 1067–1072.

    Article  Google Scholar 

  • POHL, L.R., BHOOSHAN, B., WHITTAKER, N.F. & KRISHNA, G. (1977). Phosgene: A metabolite of chloroform. Biochem. biophys. Res. Commun., 79, 684–691.

    Article  Google Scholar 

  • POHL, L.R., BRANCHFLOWER, R.V., HIGHET, R.J., MARTIN, J.L., NUNN, D.S., MONKS, T.J., GEORGE, J.W. & HINSON, J.A. (1981). The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride, Drug Metabol. Disp., 9, 334–339.

    Google Scholar 

  • POHL, L.R., GEORGE, J.W., MARTIN, J.L. & KRISHNA, G. (1979). Deuterium isotope effect in in vivo bioactivation of chloroform to phosgene. Biochem. Pharmac, 28, 561–563.

    Article  Google Scholar 

  • POHL, L.R., SCHULICK, R.D., HIGHET, R.J. & GEORGE, J.W. (1984). Reductive oxygenation mechanism of metabolism of carbon tetrachloride to phosgene by cytochrome P-450. Mol. Pharmac, 25, 318–321.

    Google Scholar 

  • POTTER, W.A., DAVIS, D.C., MITCHELL, J.R., JOLLOW, D.J., GILLETTE, J.R. & BRODIE, B.B. (1973). Acetaminophen-induced hepatic necrosis. III. Cytochrome P-450-mediated covalent binding in vitro. J. Phar-mac. exp. Ther., 187, 203–210.

    Google Scholar 

  • RECKNAGEL, R.P., GLENDE, E.A. & HRUSZKEWYCZ, A.M. (1977). Chemical mechanism in carbon tetrachloride toxicity. In Free Radicals in Molecular Biology and Pathology, Vol. III. Pryor, W.A. (ed.) pp. 97–132, New York: Academic Press.

    Google Scholar 

  • ROSEN, G.M., RAUCKMAN E.J., ELLINGTON, S.P., DAHLIN, D.C., CHRISTIE, J.L. & NELSON, S.D. (1984). Reduction and glutathione conjugation reactions of N-acetyl p-benzoquinone imine and two dimethylated analogues. Mol Pharmac, 25, 151–157.

    Google Scholar 

  • SAWAHATA, T. & NEAL, R. A. (1983). Biotransformation of phenol to hydroquinone and catechol by rat liver microsomes. Mol Pharmac, 23, 453–460.

    Google Scholar 

  • SLATER, T.F. (1982). Free radicals as reactive intermediates in tissue injury In Biological Intermediates II. Snyder, R., Parke, D.V., Kocsis, J.J., Gibson, C.G. & Witmer, CM. (eds), pp. 575–589, New York: Plenum Press.

    Chapter  Google Scholar 

  • SNYDER, R., PARKE, D.V., KOCSIS, J.J., JOLLOW, D.J., GIBSON, C.G., & WITMER, CM. (1982). Biological Intermediates II. New York: Plenum Press.

    Book  Google Scholar 

  • THOR, H., SVENSSON, S-A., HARTZELL, P. & ORRENIUS, S. (1982). Biotransformation of bromobenzene to reactive metabolites by isolated hepatocytes. In Biological Reactive Intermediates II. Snyder, R., Parke, D.V., Kocsis, J.J., Jollow, D.J., Gibson, CG. & Witmer, CM. (eds) pp. 287–299, New York: Plenum Press.

    Chapter  Google Scholar 

  • TORANZO, E.G.D. DE, DIAZ GOMEZ, M.I. & CASTRO, J. A. (1978). Carbon tetrachloride activation, lipid peroxidation and liver necrosis in different strains of mice. Res. Commun. Chem. Path. Pharmac, 19, 347–352.

    Google Scholar 

  • WOLF, CR., HARRELSON, W.G., NASTAINCZYK, W., PHILPOT, R.M., KALYANARAMAN, B. & MASON, R.P. (1980). Metabolism of carbon tetrachloride in hepatic microsomes and reconstituted monooxygenase systems and its relationship to lipid peroxidation. Mol Pharmac, 18, 553–558.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20205, USA

    J. R. Gillette, S. S. Lau, T. J. Monks & L. R. Pohl

Authors
  1. J. R. Gillette
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. S. Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. J. Monks
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. R. Pohl
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

William Paton James Mitchell Paul Turner

Copyright information

© 1984 Macmillan Publishers Limited

About this chapter

Cite this chapter

Gillette, J.R., Lau, S.S., Monks, T.J., Pohl, L.R. (1984). Free radical intermediates and liver cell necrosis. In: Paton, W., Mitchell, J., Turner, P. (eds) IUPHAR 9th International Congress of Pharmacology. Palgrave, London. https://doi.org/10.1007/978-1-349-86029-6_35

Download citation

Publish with us

Policies and ethics

Search

Navigation