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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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
CAWTHORNE, M.A., BUNYAN, J., SENNITT, M.V. & GREEN, J. (1970). Vitamin E and hepatotoxic agents. Br. J. Nutr., 24, 357–384.
CESSI, C, COLOMBINI, C. & MAMELI, L. (1966). The reaction of liver proteins with a metabolite of carbon tetrachloride. Biochem. J., 101, 46c-47c.
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.
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.
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.
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.
DIANZANI, M.U., GABRIEL, L., GRAVELA, E. & PARADISI, L. (1976). Interference of CC14 metabolites with subcellular structures. Pan. Med., 18, 310–318.
DIANZANI, M., POLI, G., GRAVELA, E., CHIARPOTTO, E. & ALBANO, E. (1981). Influence of lipid peroxidation lipoprotein secretion by isolated hepatocytes. Lipids, 16, 823–829.
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.
DIAZ GOMEZ, M.I. & CASTRO, J.A. (1980b). Nuclear activation of carbon tetrachloride and chloroform. Res. Commun. Chem. Path. Pharmac, 27, 191–194.
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.
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.
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.
DIXON, M. & WEBB, E.C. (1958). Enzymes, pp. 490–502, London: Longman.
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.
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.
FISHBEIN, L. (1976). Industrial mutagens and potential mutagens. I. Halogenated aliphatic derivatives. Mutation Res., 32, 267–308.
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.
GORDIS, E. (1969). Lipid metabolites of carbon tetrachloride. J. Clin. Invest., 48, 203–208.
HORNBROOK, K.R., POYER, J.L. & MCKAY, P.B. (1976). Lipid peroxidation in mouse liver produced by carbon tetrachloride. Pharmacologist, 18, 246.
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.
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.
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.
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.
MCLEAN, A.E. (1967a). The effect of diet and vitamin E on liver injury due to carbon tetrachloride. Br. J. Path., 48, 632–635.
MCLEAN, A.E. (1967b). Effect of hexane and carbon tetrachloride on microsomal cytochrome P-450. Biochem. Pharmac, 16, 2030–2038.
MILLER, J. A. (1970). Carcinogenesis by chemicals, an overview. (G.H. Cloves Memorial lecture.) Cancer Res., 30, 559–576.
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.
PLAA, G.L. & WITSCHI, H. (1976). Chemicals, drugs and lipid peroxidation. A. Rev. Pharmac, 16, 125–141.
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.
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.
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.
RECKNAGEL, R.O. (1983). Carbon tetrachloride hepatotoxicity: status quo and future prospects. Trends pharmac. Sei., 129–131.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
U.S. EPA (1983). Health Assessment document for carbon tetrachloride, EPA 600/8–82–001.
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.
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.
VILLARRUEL, M.C. & CASTRO, J.A. (1980). Reactions of trichloromethyl free radicals with aminoacids. Res. Commun. Chem. Path. Pharmac, 28, 79–85.
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.
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.
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.
WALLER, R.L., GLENDE, E.A. & RECKNAGEL, R.A. (1983). Carbon tetrachloride and bromotrich-loromethane toxicity. Biochem. Pharmac, 32, 1613–1617.
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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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DOI: https://doi.org/10.1007/978-1-349-86029-6_34
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