Abstract
Interest in the toxicological significance of drug metabolism has increased enormously in the last 30 years, stimulated by the growing awareness that many potentially toxic chemicals are present in our environment; and also by the appreciation that drug-metabolising reactions are not only important in detoxifying chemicals, but in many cases can actually initiate toxic responses, by converting inert drugs into biologically reactive derivatives. The enzymes that have attracted most attention in this respect are the haemoproteins of the cytochrome P-450 group which are present in the endoplasmic reticulum of the hepatocyte and of other cell types and also in the membranes of certain other organelles. Extensive work carried out in many laboratories has established that this group of cytochromes is in fact a complex family of related but not identical haemoproteins. All members of this family contain, as the active prosthetic group, protohaem (the iron complex of protoporphyrin IX) bound to the apoprotein moiety through a thiolate anion (S−) linkage from a cysteine residue, and all show the property of binding a lipid-like substrate in close proximity to the prosthetic group where the other reactant, molecular oxygen, can also bind in order to be activated (White and Coon, 1980). Oxygen activation is achieved by a stepwise addition of electrons (two per catalytic cycle) and these are donated by the satellite components of the electron transport system of the membrane (the flavoproteins and cytochrome b5) and are presumably channelled through the apoprotein and the sulphur ligand on to the iron of the haem prosthetic group (figure 8.1).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Abbritti, G. and De Matteis, F. (1973). Effect of 3,5-diethoxycarbonyl-l,4-dihydro-collidine on degradation of liver haem. Enzyme, 16, 196–202
Adams, H. R., Isaacson, E. I. and Masters, B. S. S. (1977). Inhibition of hepatic microsomal enzymes by chloramphenicol. J. Pharmacol, exptl Ther., 203, 388–96
Augusto, O., Beilan, H. S. and Ortiz de Montellano, P. R. (1982). The catalytic mechanism of cytochrome P-450: spin-trapping evidence for one-electron substrate oxidation. J. Biol. Chem., 257, 11288–95
Bernhardt, R., Makower, A., Jänig, G-R. and Ruckpaul, K. (1984). Selective chemical modification of a functionally linked lysine in cytochrome P-450 LM2. Bio-chim. Biophys. Acta, 785, 186–90
Bond, E. J. and De Matteis, F. (1969). Biochemical changes in rat liver after administration of carbon disulphide, with particular reference to microsomal changes. Biochem. Pharmacol., 18, 2531–49
Catignani, G. L. and Neal, R. A. (1975). Evidence for the formation of a protein bound hydrodisulfide resulting from the microsomal mixed function oxidase catalyzed desulfuration of carbon disulfide. Biochem. Biophys., Res. Commun., 65, 629–36
Cole, S. P. C. and Marks, G. S. (1984). Ferrochelatase and N-alkylated porphyrins. Molec. Cell. Biochem., 64, 127–37
Cole, S. P. C, Whitney, R. A. and Marks, G. S. (1981). Ferrochelatase-inhibitory and porphyrin-inducing properties of 3,5-diethoxycarbonyl-l,4-dihydro-2,4,6-trimethylpyridine and its analogues in chick embryo liver cells. Molec. Pharmacol., 20, 395–403
Correia, M. A., Farrell, G. C, Schmid, R., Ortiz de Montellano, P. R., Yost, G. S. and Mico, B. A. (1979). Incorporation of exogenous heme into hepatic cytochrome P-450 in vivo. J. Biol. Chem., 254, 15–17
Dalvi, R. R., Poore, R. E. and Neal, R. A. (1974). Studies on the metabolism of carbon disulfide by rat liver microsomes. Life Sci., 14, 1785–96
DeGroot, H. and Haas, W. (1981). Self-catalysed, O2-independent inactivation of NADPH or dithionite-reduced microsomal cytochrome P-450 by carbon tetra-chloride. Biochem. Pharmacol., 30, 2343–7
De Matteis, F. (1971). Loss of haem in rat liver caused by the porphyrogenic agent 2-allyl-2-isopropylacetamide. Biochem. J., 124, 767–77
De Matteis, F. (1974). Covalent binding of sulfur to microsomes and loss of cyto-chrome P-450 during the oxidative desulfuration of several chemicals. Molec. Pharmacol., 10, 849–54
De Matteis, F. (1978). Hepatic porphyrias caused by 2-allyl-2-isopropylacet-amide, 3,5-diethoxycarbonyl-1,4-dihydrocollidine, Griseofulvin and related compounds. Handbook exptl Pharmacol., 44, 129–55
De Matteis, F. and Cantoni, L. (1979). Alteration of the porphyrin nucleus of cytochrome P-450 caused in the liver by treatment with allyl-containing drugs. Is the modified porphyrin TV-substituted? Biochem. J., 183, 99–103
De Matteis, F. and Gibbs, A. H. (1980). Drug-induced conversion of liver haem into modified porphyrins. Evidence for two classes of products. Biochem. J., 187, 285–8
De Matteis, F. and Seawright, A. A. S. (1973). Oxidative metabolism of carbon disulphide by the rat. Effect of treatments which modify the liver toxicity of carbon disulphide. Chem. Biol. Interact., 7, 375–88
De Matteis, F., Gibbs, A. H., Cantoni, L. and Francis, J. (1980a). Substrate-dependent irreversible inactivation of cytochrome P-450: conversion of its haem moiety into modified porphyrins. In: Ciba Foundation 76 (New Series), Amsterdam, Excerpta Medica, pp. 119–31
De Matteis, F., Gibbs, A. H., Jackson, A. H. and Weerasinghe, S. (1980b). Conversion of liver haem into N-substituted porphyrins or green pigments. Nature of the substituent at the pyrrole nitrogen atom. FEBS Lett., 119, 109–12
De Matteis, F., Gibbs, A. H. and Smith, A. G. (1980c). Inhibition of protohaem ferro-lyase by N-substituted porphyrins. Structural requirements for the inhibitory effect. Biochem. J., 189, 645–8
De Matteis, F., Gibbs, A. H. and Tephly, T. R. (1980d). Inhibition of protohaem ferro-lyase in experimental porphyria. Isolation and partial characterization of a modified porphyrin inhibitor. Biochem. J., 188, 145–52
De Matteis, F., Gibbs, A. H., Farmer, P. B. and Lamb, J. H. (1981). Liver production of N-alkylated porphyrins caused in mice by treatment with substituted dihydropyridines. Evidence that the alkyl group on the pyrrole nitrogen atom originates from the drug. FEBS Lett., 129, 328–31
De Matteis, F., Gibbs, A. H. and Unseld, A. P. (1982a). Conversion of liver haem into N-substituted porphyrins or green pigments. Evidence for two distinct classes of products. In: Biological Reactive Intermediates 2 (ed. R. Snyder), New York, Plenum Press, pp. 1319–34
De Matteis, F., Holland, C, Gibbs, A. H., De Sa, N. and Rizzardini, M. (1982b). Inactivation of cytochrome P-450 and production of N-alkylated porphyrins caused in isolated hepatocytes by substituted dihydropyridines. Structural requirements for loss of haem and alkylation of the pyrrole nitrogen atom. FEBS Lett., 145, 87–92
De Matteis, F., Jackson, A. H., Gibbs, A. H., Rao, K. R. N., Atton, J., Weerasinghe, S. and Hollands, C. (1982c). Structural isomerism and chirality of N-monosub-stituted protoporphyrins. FEBS Lett., 142, 44–8
De Matteis, F., Gibbs, A. H. and Hollands, C. (1983). N-Alkylation of the haem moiety of cytochrome P-450 caused by substituted dihydropyridines. Preferential attack of different pyrrole nitrogen atoms after induction of various cytochrome P-450 isoenzymes. Biochem. J., 211, 455–61
Elcombe, C. R., Bridges, J. W., Gray, T. J. B., Nimmo-Smith, R. H. and Netter, K. J. (1975). Studies on the interaction of safrole with rat hepatic microsomes. Biochem. Pharmacol., 24, 1427–33
Fermi, G. and Perutz, M. (1981). Atlas of Molecular Structures in Biology, Vol. 2, Hemoglobin and Myoglobin, Oxford University Press, New York
Freundt, K. J. and Dreher, W. (1969). Inhibition of drug metabolism by small concentrations of carbon disulphide. Naunym-Schmiedebergs Arch. Pharmakol. exp. Path., 263, 208–9
Gan, L-S. L., Acebo, A. L. and Alworth, W. L. (1984). 1-ethynylpyrene, a suicide inhibitor of cytochrome P-450 dependent benz[a]pyrene hydroxylase activity in liver microsomes. Biochemistry, 23, 3827–36
Halpert, J. (1981). Covalent modification of lysine during the suicide inactivation of rat liver cytochrome P-450 by chloramphenicol. Biochem. Pharmacol., 30, 875–81
Halpert, J. (1982). Further studies of the suicide inactivation of purified rat liver cytochrome P-450 by chloramphenicol. Molec. Pharmacol., 21, 166–72
Halpert, J. R. and Neal, R. A. (1980). Inactivation of purified rat liver cytochrome P-450 by chloramphenicol. Molec. Pharmacol, 17, 427–31
Halpert, J., Hammond, D. and Neal, R. A. (1980). Inactivation of purified rat liver cytochrome P-450 during metabolism of parathion (diethyl-p-nitrophenyl phosphorothionate). J. Biol. Chem., 255, 1080–9
Halpert, J. R., Miller, N. E. and Gorsky, L. D. (1985). On the mechanism of the inactivation of the major phenobarbital-inducible isozyme of rat liver cytochrome P-450 by chloramphenicol. J. Biol Chem., 260, 8397–403
Hanzlik, R. P. and Tullman, R. H. (1982). Suicidal inactivation of cytochrome P-450 by cyclopropylamines. Evidence for cation-radical intermediates. J. Am. chem. Soc, 104, 2048–50
Järvisalo, J., Gibbs, A. H. and De Matteis, F. (1978). Accelerated conversion of heme to bile pigments caused in the liver by carbon disulfide and other sulfur-containing chemicals. Molec. Pharmacol., 14, 1099–106
Jonen, H. G., Werringloer, J., Prough, R. A. and Estabrook, R. W. (1982). The reaction of phenylhydrazine with microsomal cytochrome P-450. Catalysis of heme modification. J. Biol. Chem., 257, 4404–11
Kamataki, T. and Neal, R. A. (1976). Metabolism of diethyl p-nitrophenyl phos-phorothionate (Parathion) by a reconstituted mixed-function oxidase enzyme system: studies of the covalent binding of the sulphur atom. Molec. Pharmacol., 12, 933–44
Kikuchi, G., Yoshida, T. and Ishizawa, S. (1982). Effect of drugs and metals on heme degradation by the heme oxygenase system. Adv. Pharmacol Ther. Proc. Int. Congr. 8th, 5, 121–30
Kunz, B. C. and Richter, C. (1983). Chemical modification of microsomal cytochrome P-450: role of lysyl residues in hydroxylation activity. FEBS Lett., 161, 311–14
Kunze, K. L., Mangold, B. L. K., Wheeler, C, Beilan, H. S. and Ortiz de Montellano, P. R. (1983). The cytochrome P-450 active site. Regiospecificity of prosthetic heme alkylation by Olefins and Acetylenes. J. Biol Chem., 258, 4202–7
Levin, W. and Kuntzmann, R. (1969). Biphasic decrease of radioactive hemoprotein from liver microsomal CO-binding particles. Effect of 3-methylcholanthrene. J. Biol Chem., 244, 3671–6
Levin, M., Jacobson, M., Sernatinger, E. and Kuntzman, R. (1973). Breakdown of cytochrome P-450 heme by secobarbital and other allyl-containing barbiturates. Drug Metab. Dispos., 1, 275–84
Loev, B. and Snader, K. M. (1965). The Hantzsch Reaction. I. Oxidative dealkylation of certain dihydropyridines. J. Org. Chem., 30, 1914–16
Loosemore, M. J., Wogan, G. N. and Walsh, C. (1981). Determination of partition ratios for allylisopropylacetamide during suicidal processing by a phenobarbi-
tone-induced cytochrome P-450 isozyme from rat liver. J. Biol Chem., 256, 8705–12
Lu, A. Y. H. and West, S. B. (1980). Multiplicity of mammalian microsomal cyto-crome P-450. Pharmacol. Rev., 31, 277–95
Macdonald, T. L., Zirvi, K., Burka, L. T., Peyman, P. and Guengerich, F. P. (1982). Mechanism of cytochrome P-450 inhibition by cyclopropylamines. J. Am. chem. Soc, 104, 2050–2
Marks, G. S., Allen, D. T., Johnston, C. T., Sutherland, E. P., Nakatsu, K. and Whitney, R. A. (1985). Suicidal destruction of cytochrome P-450 and reduction of ferrochelatase activity by 3,5-diethoxycarbonyl-l,4-dihydro-2,4,6-trimethyl-pyridine and its analogues in chick embryo liver cells. Molec. Pharmacol., 27, 459–65
Menard, R. H., Guenthner, T. M., Kon, H. and Gillette, J. R. (1979). Studies on the destruction of adrenal and testicular cytochrome P-450 by spironolactone. Requirement for the 7α-thio group and evidence for the loss of heme and apo-proteins of cytochrome P-450. J. Biol Chem., 254, 1726–33
Metcalf, B. W., Wright, C. L., Burkhart, J. P. and Johnston, J. O. (1981). Substrate-induced inactivation of aromatase by allenic and acetylenic steroids. J. Am. chem. Soc, 103, 3221–2
Miki, N., Sugiyama, T. and Yamano, T. (1980). Purification and characterization of cytochrome P-450 with high affinity for cytochrome b5. J. Biochem., 88, 307–16
Morelli, M. A. and Nakatsugawa, T. (1978). Inactivation in vitro of microsomal oxidases during parathion metabolism. Biochem. Pharmacol., 27, 293–9
Nagahisa, A., Spencer, R. W. and Orme-Johnson, W. H. (1983). Acetylenic mechanism-based inhibitors of cholesterol side chain cleavage by cytochrome P-450scc. J. Biol. Chem., 258, 6721–3
Nakatsugawa, T., Tolman, N. M. and Dahm, P. A. (1968). Degradation and activation of parathion analogues by microsomal enzymes. Biochem. Pharmacol, 17, 1517–28
Neal, R. A. (1980). Microsomal metabolism of thiono-sulfur compounds: mechanisms and toxicological significance. Rev. Biochem. Toxicol., 2, 131–71
Ortiz de Montellano, P. R. and Correia, M. A. (1983). Suicidal destruction of cytochrome P-450 during oxidative drug metabolism. Ann. Rev. Pharmacol. Toxicol., 23, 481–503
Ortiz de Montellano, P. R. and Kunze, K. L. (1981). Cytochrome P-450 inactivation: Structure of the prosthetic heme adduct with propyne. Biochemistry, 20, 7266–71
Ortiz de Montellano, P. R. and Mico, B. A. (1981). Destruction of cytochrome P-450 by allylisopropylacetamide is a suicidal process. Arch. Biochem. Biophys., 206, 43–50
Ortiz de Montellano, P. R. and Reich, N. O. (1984). Specific inactivation of hepatic fatty acid hydroxylases by acetylenic fatty acids. J. Biol. Chem., 259, 4136–41
Ortiz de Montellano, P. R., Mico, B. A. and Yost, G. S. (1978). Suicidal inactivation of cytochrome P-450. Formation of a heme-substrate covalent adduct. Biochem. Biophys. Res. Commun., 83, 132–7
Ortiz de Montellano, P. R., Kunze, K. L., Yost, G. S. and Mico, B. A. (1979). Self-catalyzed destruction of cytochrome P-450: Covalent binding of ethynyl sterols to prosthetic heme. Proc. Nat. Acad. Sci. USA, 76, 746–9
Ortiz de Montellano, P. R., Beilan, H. S. and Kunze, K. L. (1981a). N-Alkylproto-porphyrin IX: Formation in 3,5-dicarbethoxy-1,4-dihydrocollidine-treated rats. Transfer of the alkyl groups from the substrate to the porphyrin. J. Biol Chem., 256, 6708–13
Ortiz de Montellano, P. R., Beilan, H. S., Kunze, K. L. and Mico, B. A. (1981b). Destruction of cytochrome P-450 by ethylene. Structure of the resulting prosthetic heme adduct. J. Biol. Chem., 256, 4395–9
Ortiz de Montellano, P. R., Mico, B. A., Mathews, J. M., Kunze, K. L., Miwa, G. T. and Lu, A. Y. H. (1981c). Selective inactivation of cytochrome P-450 iso-enzymes by suicide substrates. Arch. Biochem. Biophys., 210, 717–28
Ortiz de Montellano, P. R., Beilan, H. S. and Kunze, K. L. (1981d). N-Methyl-protoporphyrin IX: Chemical synthesis and identification as the green pigment produced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine treatment. Proc. Nat. Acad. Sci. USA, 78, 1490–4
Ortiz de Montellano, P. R., Kunze, K. L. and Beilan, H. S. (1983a). Chiral orientation of prosthetic heme in the cytochrome P-450 active site. J. Biol. Chem., 258, 45–7
Ortiz de Montellano, P. R., Mangold, B. L. K., Wheeler, C, Kunze, K. L. and Riech, N. O. (1983b). Stereochemistry of cytochrome P-450-catalyzed epoxidation and prosthetic heme alky lat ion. J. Biol Chem., 258, 4208–13
Pohl, L. R. and Krishna, G. (1978). Study of the mechanism of metabolic activation of chloramphenicol by rat liver microsomes. Biochem. Pharmacol, 27, 335–41
Pohl, L. R., Nelson, S. D. and Krishna, G. (1978). Investigation of the mechanism of the metabolic activation of chloramphenicol by rat liver microsomes. Identification of a new metabolite. Biochem. Pharmacol, 27, 491–6
Poore, R. E. and Neal, R. A. (1972). Evidence for extrahepatic metabolism of parathion. Toxicol. appl. Pharmacol., 23, 759–68
Ptashne, K. A., Wolcott, R. M. and Neal, R. A. (1971). Oxygen-18 studies on the chemical mechanisms of the mixed function oxidase catalysed desulfuration and dearylation reactions of parathion. J. Pharmacol. exptl. Ther., 179, 380–5
Schwartz, S. and Ikeda, K. (1955). Studies of porphyrin synthesis and interconversion, with special reference to certain green porphyrins in animals with experimental hepatic porphyria. In: Ciba Foundation Symp: Porphyrin Biosynthesis and Metabolism (ed. G. E. W. Wolstenholme), J. & A. Churchill, London, pp. 209–26
Tephly, T. R., Gibbs, A. H. and De Matteis, F. (1979). Studies on the mechanism of experimental porphyria produced by 3,5-diethoxycarbonyl-1,4-dihydro-collidine. Role of a porphyrin-like inhibitor of protohaem ferro-lyase. Biochem. J., 180, 241–4
Tephly, T. R., Coffman, B. L., Ingall, G., Abou Zeit-Har, M. S., Goff, H. M., Tabba, H. D. and Smith, K. M. (1981). Identification of N-methylprotoporphyrin IX in livers of untreated mice and mice treated with 3,5-diethoxycarbonyl-1,4-di-hydrocollidine: source of the methyl group. Arch. Biochem. Biophys., 212, 120–6
Unseld, A. and De Matteis, F. (1978). Destruction of endogenous and exogenous haem by 2-allyl-2-isopropylacetamide: role of the liver cytochrome P-450 which is inducible by phenobarbitone. Int. J. Biochem., 9, 865–9
Wada, O., Yano, Y., Urata, G. and Nakao, K. (1968). Behaviour of hepatic micro-somal cytochromes after treatment of mice with drugs known to disturb por-phyrin metabolism in liver. Biochem. Pharmacol., 17, 595–603
Waxman, D. J. and Walsh, C. (1982). Phenobarbital-induced rat liver cytochrome P-450: purification and characterization of two closely related isozymic forms. J. Biol. Chem., 257, 10446–57
White, I. N. H. (1978). Metabolic activation of acetylenic substituents to derivatives in the rat causing the loss of hepatic cytochrome P-450 and haem. Biochem. J., 174, 853–61
White, I. N. H. (1981). Destruction of liver haem by norethindrone. Conversion into green pigments. Biochem. J., 196, 575–83
White, I. N. H. (1982). Biliary excretion of green pigments produced by norethindrone in the rat. Biochem. Pharmacol., 31, 1337–42
White, I. (1984). Suicidal destruction of cytochrome P-450 by ethynyl substituted compounds. Pharmaceut. Res., 141–88
White, R. E. and Coon, M. J. (1980). Oxygen activation by cytochrome P-450. Ann. Rev. Biochem., 49, 315–56
White, I. N. H. and Muller-Eberhard, U. (1977). Decreased liver cytochrome P-450 in rats caused by norethindrone or ethynyloestradiol. Biochem. J., 166, 57–64
Copyright information
© 1987 F. De Matteis
About this chapter
Cite this chapter
De Matteis, F. (1987). Drugs as Suicide Substrates of Cytochrome P-450. In: Selectivity and Molecular Mechanisms of Toxicity. Palgrave Macmillan, London. https://doi.org/10.1007/978-1-349-08759-4_8
Download citation
DOI: https://doi.org/10.1007/978-1-349-08759-4_8
Publisher Name: Palgrave Macmillan, London
Print ISBN: 978-1-349-08761-7
Online ISBN: 978-1-349-08759-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)