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Mechanistical studies and prevention of free radical cell injury

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IUPHAR 9th International Congress of Pharmacology

Abstract

In this review, I plan to analyse addition reactions of free radicals with cellular constituents, and their possible relevance in free radical induced cell injury. To illustrate this point, I selected the case of CCl4 induced liver cell injury. Why CCl4? The reason is that CCl4 is perhaps the toxin that has been studied most thoroughly in this regard, and has been considered by many workers as a very useful model hepatotoxin.

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References

  • ALBANO, E., LOIT, K., SLATER, T.F., STIER, A., SYMONS, M.C. & TOMASI, A. (1982). Spin-trapping studies on the free-radical products formed by metabolic activation of carbon tetrachloride in rat liver microsomal fractions, isolated hepatocytes and in vivo in the rat. Biochem. J., 204, 593–603.

    Article  Google Scholar 

  • ALBERTS, B., BRAY, D., LEWIS, J., RAFF, M., ROBERTS, K. & WATSON, J.D. (1983). In Molecular Biology of the Cell, pp. 255–263, New York: Garland Publishing.

    Google Scholar 

  • ANSARI, G.A., MOSLEN, M.T. & REYNOLDS, E.S. (1982). Evidence for in vivo covalent binding of CC13 derived from CCI4 to cholesterol of rat liver. Biochem. Pharmacol, 3509–3510.

    Google Scholar 

  • BERNACCHI, A.S., CASTRO, CR. DE, TORANZO, E.G.D. DE, MARZI, A., FERREYRA, E.C. DE, FENOS, O.M. DE & CASTRO, J.A. (1980). Pyrazole prevention of CCV induced ultrastructural changes in rat liver. Br. J. exp. Path., 61, 505–511.

    Google Scholar 

  • BROOKES, P. (1966). Quantitative aspects of the reaction of some carcinogens with nucleic acids and the possible significance of such reactions in the process of carcinogenesis. Cancer Res., 26,1944–2003.

    Google Scholar 

  • CALLEN, D.F., WOLF, C.R. & PHILPOT, R.M. (1980). Cytochrome P-450 mediated genetic activity and cytotoxicity of seven halogenated aliphatic hydrocarbons in Saccharomyces cerevisiae. Mutation Res., 77, 55–63.

    Article  Google Scholar 

  • CASTRO, CR. DE, BERNACCHI, A.S., FERREYRA, E.C. DE, FENOS, O.M. DE & CASTRO, J.A. (1978). Carbon tetrachloride induced ultrastructural alterations in pancreatic acinar cells and in the hepatocytes. Similarities and differences. Toxicology, 11, 289–296.

    Article  Google Scholar 

  • CASTRO, J.A., CASTRO, CR. DE, D’ACOSTA, N., DIAZ GOMEZ, M.I. & FERREYRA, E.C. DE (1973a). Carbon tetrachloride activation in liver microsomes from rats induced with 3-methylcholanthrene. Biochem. biophys. Res. Commun. 50, 273–279.

    Article  Google Scholar 

  • CASTRO, J.A., CASTRO, CR. DE, FENOS, O.M. DE, FERREYRA, E.C. DE DIAZ GOMEZ, M.C. & D’ACOSTA, N. (1972a). Effect of cystamine on the mixed function oxygenase system from rat liver microsomes and preventive effect on the destruction of cytochrome P-450 by carbon tetrachloride. Pharmac. Res. Commun, 4, 185–190.

    Article  Google Scholar 

  • CASTRO, J.A. & DIAZ GOMEZ, M.I. (1972). Studies on the irreversible binding of 14CC14 to microsomal lipids in rats under varying experimental conditions. Toxic, appl. Pharmac, 23, 541–552.

    Article  Google Scholar 

  • CASTRO, J.A. & DIAZ GOMEZ, M.I. (1976). Further studies on the mechanism of the carbon tetrachloride-induced polysome breakdown. Res. Commun. Chem. Path. Pharmac, 13, 731–741.

    Google Scholar 

  • CASTRO, J.A., DIAZ GOMEZ, M.I., CASTRO, CR. DE, FENOS, O.M. DE, FERREYRA, E.C. DE & D’ACOSTA, N (1975). Carbon tetrachloride-induced polysome breakdown. Relative importance of lipid peroxidation and of binding to ribosomal components in the process. Res. Commun. Chem. Path. Pharmac, 10, 93–104.

    Google Scholar 

  • CASTRO, J.A., DIAZ GOMEZ, M.I., FERREYRA, E.C., DE, CASTRO, CR. DE, D’ACOSTA, N. & FENOS, O.M. DE (1973). Carbon tetrachloride effect on rat liver and adrenals related to the mixed-function oxygenase content. Biochem. biophys. Res. Commun, 47, 315–321.

    Article  Google Scholar 

  • CASTRO, J.A., DIAZ GOMEZ, M.I., FERREYRA, E.C. DE, CASTRO, CR. DE, D’ACOSTA, N. & FENOS, O.M. DE (1973b). Differences in the carbon tetrachloride-induced damage to components of the smooth and rough endoplasmic reticulum from rat liver. Biochem. biophys. Res. Commun, 50, 337–343.

    Article  Google Scholar 

  • CASTRO, J.A., FERREYRA, E.C. DE, CASTRO, CR. DE, DIAZ GOMEZ, M.I., D’ACOSTA, N. & FENOS, O.M. DE (1973c). Studies on the mechanism of cystamine prevention of several liver structural biochemical alterations caused by carbon tetrachloride. Toxic, appl. Pharmac, 24, 1–19.

    Article  Google Scholar 

  • CASTRO, J.A., SASAME, H.A., SUSSMAN, H. & GILLETTE, J.R. (1968). Diverse effects of SKF 525 A and antioxidants on carbon tetrachloride induced changes in liver microsomal P-450 content and ethylmorphine metabolism. Life Sei., 7, 129–136.

    Article  Google Scholar 

  • CAWTHORNE, M.A., BUNYAN, J., SENNITT, M.V. & GREEN, J. (1970). Vitamin E and hepatotoxic agents. Br. J. Nutr., 24, 357–384.

    Article  Google Scholar 

  • CESSI, C, COLOMBINI, C. & MAMELI, L. (1966). The reaction of liver proteins with a metabolite of carbon tetrachloride. Biochem. J., 101, 46c-47c.

    Article  Google Scholar 

  • CICCOLI, L., CASINI, A.F. & BENEDETTI, A. (1978). Free radical damage produced by carbon tetrachloride in lipids of various rat tissues. Agents and Actions, 8, 303–310.

    Article  Google Scholar 

  • CIGNOLI, E.V. & CASTRO, J.A. (1971). Lipid peroxidation, necrosis and the in vivo depression of liver glucose-6-phosphatase by carbon tetrachloride. Exp. mol. Path., 14, 43–56.

    Article  Google Scholar 

  • D’ACOSTA, N., CASTRO, J.A., FERREYRA, E.C. DE, DIAZ GOMEZ, M.I. & CASTRO, CR. DE (1972). Pyrazole blockade of carbon tetrachloride activation and liver necrosis. Res. Commun. Chem. Path. Pharmac, 4, 641–650.

    Google Scholar 

  • DE GROOT, H. & HAAS, W. (1981). Self-catalysed, 02-independent inactivation of NADPH or dithionite-reduced microsomal cytochrome P-450 by carbon tetrachloride. Biochem. Pharmac, 30, 2343–2347.

    Article  Google Scholar 

  • DIANZANI, M.U., GABRIEL, L., GRAVELA, E. & PARADISI, L. (1976). Interference of CC14 metabolites with subcellular structures. Pan. Med., 18, 310–318.

    Google Scholar 

  • DIANZANI, M., POLI, G., GRAVELA, E., CHIARPOTTO, E. & ALBANO, E. (1981). Influence of lipid peroxidation lipoprotein secretion by isolated hepatocytes. Lipids, 16, 823–829.

    Article  Google Scholar 

  • DIAZ GOMEZ, M.I. & CASTRO, J.A. (1980a). Covalent binding of carbon tetrachloride to liver nuclear DNA, proteins and lipids. Toxic, appl. Pharmac, 56, 199–206.

    Article  Google Scholar 

  • DIAZ GOMEZ, M.I. & CASTRO, J.A. (1980b). Nuclear activation of carbon tetrachloride and chloroform. Res. Commun. Chem. Path. Pharmac, 27, 191–194.

    Google Scholar 

  • DIAZ GOMEZ, M.I. & CASTRO, J.A. (1981). Reaction of trichloromethyl free radicals with deoxyribonucleic acid bases. Res. Commun. Chem. Path. Pharmac, 32, 147–153.

    Google Scholar 

  • DIAZ GÖMEZ, M.I., CASTRO, J.A., CASTRO, CR. DE, D’ACOSTA, N., FENOS, O.M. DE & FERREYRA, E.C. DE (1975). Species differences in carbon tetrachloride-induced hepatotoxicity. The role of CCI4 activation and of lipid peroxidation. Toxic, appl. Pharmac, 34, 102–114.

    Article  Google Scholar 

  • DIAZ GOMEZ, M.I., CASTRO, J.A., FERREYRA, E.C. DE, D’ACOSTA, N. & CASTRO, CR. DE (1973). Irreversible binding of 14C from 14CC14 to liver microsomal lipids and proteins from rats pretreated with compounds altering microsomal mixed-function oxygenase activity. Toxic. appl. Pharmac, 25, 534–541.

    Article  Google Scholar 

  • DIXON, M. & WEBB, E.C. (1958). Enzymes, pp. 490–502, London: Longman.

    Google Scholar 

  • FERNANDEZ, G., VILLARRUEL, M.C., TORANZO, E.G.D. DE & CASTRO, J. A. (1982). Covalent binding of carbon tetrachloride metabolites to the heme moiety of cytochrome P-450 and its degradation products. Res. Commun. Chem. Path. Pharmac, 35, 283–290.

    Google Scholar 

  • FERREYRA, E.C. DE, CASTRO, J.A., DIAZ GOMEZ, M.I., D’ACOSTA, N., CASTRO, CR. DE & FENOS, O.M. DE (1975). Diverse effects of antioxidants on carbon tetrachloridehepatotoxicity. Toxic, appl. Pharmac, 32, 504–512.

    Article  Google Scholar 

  • FISHBEIN, L. (1976). Industrial mutagens and potential mutagens. I. Halogenated aliphatic derivatives. Mutation Res., 32, 267–308.

    Article  Google Scholar 

  • GLENDE, E.A., HURSZKEWYCZ, A.M. & RECKNAGEL, R.O. (1976). Critical role of lipid peroxidation in carbon tetrachloride-induced loss of aminopyrine demethylase, cytochrome P-450 and glucose-6-phosphatase. Biochem. Pharmac, 21, 1697–1702.

    Article  Google Scholar 

  • GORDIS, E. (1969). Lipid metabolites of carbon tetrachloride. J. Clin. Invest., 48, 203–208.

    Article  Google Scholar 

  • HORNBROOK, K.R., POYER, J.L. & MCKAY, P.B. (1976). Lipid peroxidation in mouse liver produced by carbon tetrachloride. Pharmacologist, 18, 246.

    Google Scholar 

  • KITTA, D., SCHWARZ, M., TENNEKES, H.A., UEHLEKE, H. & KUNZ, W. (1982). Covalent binding of CCl4-intermediates to reduced pyridine nucleotides in mouse liver. In Biological Reactive Intermediates, vol II, Snyder, R. (ed.), pp. 769–777, New York: Plennum Press.

    Chapter  Google Scholar 

  • LAI, E.K., MCKAY, P.B., NOGUCHI, T. & FOG, K.L. (1979). In vivo spin trapping of trichloromethyl radicals formed from CCI4. Biochem. Pharmac, 28, 2231–2235.

    Article  Google Scholar 

  • LEE, P.Y., MCCAY, P.B. & HORNBROOK, K.R. (1982). Evidence for carbon tetrachloride-induced lipid peroxidation in mouse liver. Biochem. Pharmac, 31, 405–409.

    Article  Google Scholar 

  • MASON, R.P. (1982). Free radical intermediates in the metabolism of toxic chemicals. In Free Radicals in Biology, vol. V, Pryor, W.A. (ed.), pp. 161–221, New York: Academic Press.

    Google Scholar 

  • MCLEAN, A.E. (1967a). The effect of diet and vitamin E on liver injury due to carbon tetrachloride. Br. J. Path., 48, 632–635.

    Google Scholar 

  • MCLEAN, A.E. (1967b). Effect of hexane and carbon tetrachloride on microsomal cytochrome P-450. Biochem. Pharmac, 16, 2030–2038.

    Article  Google Scholar 

  • MILLER, J. A. (1970). Carcinogenesis by chemicals, an overview. (G.H. Cloves Memorial lecture.) Cancer Res., 30, 559–576.

    Google Scholar 

  • NAYAK, N.C. & CHOPRA, P. (1980). Carbon tetrachloride toxicity, failure of promethazine to prevent in vivo liver injury. Indian J. Med. Res., 72, 546–553.

    Google Scholar 

  • PLAA, G.L. & WITSCHI, H. (1976). Chemicals, drugs and lipid peroxidation. A. Rev. Pharmac, 16, 125–141.

    Article  Google Scholar 

  • POLI, G. & GRAVELA, E. (1982). Lipid peroxidation in isolated hepatocytes. In Free Radicals, Lipid Peroxidation and Cancer McBrien, D.C. & Slater, T.F. (eds), pp. 215–234, New York: Academic Press.

    Google Scholar 

  • POYER, J.L, FLOYD, R.A., MCCAY, P.B., JANZEN, E.G. & DAVIS, E.R. (1978). Spin-trapping of the trichloromethyl radical produced during enzymatic NADPH oxidation in the presence of carbon tetrachloride or bromotrichloromethane. Biochem. biophys. Acta, 539, 402–409.

    Article  Google Scholar 

  • RAO, K.S. & RECKNAGEL, R.O. (1969). Early incorporation of carbon labelled carbon tetrachloride into rat liver particulate lipids and proteins. Exp. molec Path., 10, 219–228.

    Article  Google Scholar 

  • RECKNAGEL, R.O. (1983). Carbon tetrachloride hepatotoxicity: status quo and future prospects. Trends pharmac. Sei., 129–131.

    Google Scholar 

  • REYNOLDS, E.S. (1967). Liver parenchymal cell injury: IV. Pattern of incorporation of carbon and chlorine from carbon tetrachloride into chemical constituents of liver in vivo. J. Pharmac. exp. Ther., 155, 117–126.

    Google Scholar 

  • REYNOLDS, E.S. & YEE, A.G. (1967). Liver parenchymal cell injury: V. Relationships between patterns of chloromethane. 14C incorporation into constituents of liver in vivo and cellular injury. Lab. Invest., 16, 591–603.

    Google Scholar 

  • ROCCHI, P., PRODI, G., GRILLI, S. & FERRERI, A.M. (1973). In vivo and in vitro binding of carbon tetrachloride with nucleic acids and proteins in rat and mouse liver. Int. J. Cancer, 11, 419–425.

    Article  Google Scholar 

  • SASAME, H., CASTRO, J.A. & GILLETTE, J.R. (1968). Studies on the destruction of liver microsomal cytochrome P-450 by carbon tetrachloride administration. Biochem. Pharmac, 17, 1759–1768.

    Article  Google Scholar 

  • SLATER, T.F. (1982). Activation of carbon tetrachloride: chemical principles and biological significance. In Free Radicals, Lipid Peroxidation and Cancer, McBrien, D.C. & Slater, T.F. (eds), pp. 243–270, New York: Academic Press.

    Google Scholar 

  • TORANZO, E.G.D. DE, DIAZ GOMEZ, M.I. & CASTRO, J.A. (1975). Mechanism of in vivo carbon tetrachloride-induced liver microsomal cytochrome P-450 destruction. Biochem. biophys. Res. Commun., 64, 823–828.

    Article  Google Scholar 

  • TORANZO, E.G.D. DE, MARZI, A. & CASTRO, J.A. (1980). Promethazine administration to rats and CCLrinduced lipid peroxidation of liver microsomal lipids. Res. Commun. Chem. Path. Pharmac, 30, 91–98.

    Google Scholar 

  • TORANZO, E.G.D. DE, VILLARRUEL, M.C. & CASTRO, J.A. (1978). Early destruction of cytochrome P-450 in testis of carbon tetrachloride poisoned rats. Toxicology, 10, 39–44.

    Article  Google Scholar 

  • TRUDELL, J.R., BÖSTERLING, R. & TREVOR, A.J. (1982). Reductive metabolism of carbon tetrachloride by human cytochrome P-450 reconstituted in phospholipid vesicles: Mass spectral identification of trichloromethyl radicals bound to dioleyl phosphatidylcholine. Proc Nat. Acad. Sei. USA, 79, 2678–2686.

    Article  Google Scholar 

  • UEHLEKE, H., HELLMER, K., & TABARELLI, S. (1973). Binding of 14C-carbon tetrachloride to microsomal proteins in vitro and formation of CHCl3 by reduced liver ribosomes. Xenobiotica, 3, 1–11.

    Article  Google Scholar 

  • U.S. EPA (1983). Health Assessment document for carbon tetrachloride, EPA 600/8–82–001.

    Google Scholar 

  • VILLARRUEL, M.C. & CASTRO, J.A. (1973). Carbon tetrachloride target lipids in rat liver microsomes. Effect of cystamine administration on their pattern of labelling by CCI4. Biochem. biophys. Res. Commun., 54, 108–115.

    Article  Google Scholar 

  • VILLARRUEL, M.C. & CASTRO, J.A. (1975). Irreversible binding of carbon tetrachloride to microsomal phospholipids. Free radical nature of the reactive specie and alterations in the physico-chemical properties of the target fatty acids. Res. Commun. Chem. Path. Phar-mac, 10, 105–116.

    Google Scholar 

  • VILLARRUEL, M.C. & CASTRO, J.A. (1980). Reactions of trichloromethyl free radicals with aminoacids. Res. Commun. Chem. Path. Pharmac, 28, 79–85.

    Google Scholar 

  • VILLARRUEL, M.C, DIAZ GOMEZ, M.I. & CASTRO, J.A. (1975). The nature of the in vitro irreversible binding of carbon tetrachloride to microsomal lipids. Toxic, appl. Pharmac, 33, 106–114.

    Article  Google Scholar 

  • VILLARRUEL, M.C, TORANZO, E.G.D. DE & CASTRO, J.A. (1977). Carbon tetrachloride activation, lipid peroxidation and the mixed function oxygenase activity of various rat tissues. Toxic, appl. Pharmac, 41, 337–344.

    Article  Google Scholar 

  • VILLARRUEL, M.C, TORANZO, E.G.D. DE & CASTRO, J.A. (1976). CC14 administration to strain A/J mice or rats and the arachidonic acid content of their liver microsomal phospholipids. Res. Commun. Chem. Path. Pharmac, 14, 193–196.

    Google Scholar 

  • WALLER, R.L., GLENDE, E.A. & RECKNAGEL, R.A. (1983). Carbon tetrachloride and bromotrich-loromethane toxicity. Biochem. Pharmac, 32, 1613–1617.

    Article  Google Scholar 

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  1. Centro de Investigaciones Toxicológicas (CEITOX)-CITEFA/CONICET, Zufriategui 4380, 1603 Villa Martelli, Pcia. de Buenos Aires, Argentina

    J. A. Castro

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  1. J. A. Castro
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William Paton James Mitchell Paul Turner

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© 1984 Macmillan Publishers Limited

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Castro, J.A. (1984). Mechanistical studies and prevention of free radical cell injury. 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_34

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