Abstract
It was suggested in 1971 based on studies with the hepatotoxic agent, bromobenzene, that metabolism of chemicals to reactive intermediates could play a central role in toxicological processes involved with xenobiotics (Brodie et al., 1971). Over the subsequent 20 years, studies on a variety of chemicals have supported such a notion due to the correlation of the level of protein bound metabolites with toxicity (Hinson & Roberts, 1992). Only in a few cases, however, have the proteins involved or the nature of the covalent modifications been determined and in no case has a direct toxicological role for the altered proteins been shown. One of the best characterized cellular targets of reactive intermediates are the liver microsomal P450 cytochromes (Ortiz de Montellano & Correia, 1983; Halpert & Stevens, 1991), which in many instances are the enzymes responsible for the generation of the reactive metabolites. It is known that at least three pathways exist for the covalent alteration of the cytochrome P450, one that involves alteration of the heme, a second that involves alteration of the protein, and a third that involves the crosslinking of heme to the protein (Scheme I) (Osawa & Pohl, 1989). Although the alterations of the heme or the protein have been well documented (Ortiz de Montellano, 1990; Halpert, 1982; Halpert, Miller, & Gorsky, 1985; Roberts et al., 1994; Roberts, Hopkins, Alworth, & Hollenberg, 1993; Bryant, Skipper, Tannenbaum, & Maclure, 1987; Gorelick, Hutchins, Tannenbaum, & Wogan, 1989), the protein bound heme adducts have not been structurally defined, due to the complexity of the cytochrome P450 system and the potential reactions that can occur after initial heme alteration.
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
Arduini, A., Mancinelli, G., Radatti, G.L., Damonti, W., Hochstein, P., & Cadenas, E. (1992). Reduction of sperm whale ferrylmyoglobin by endogenous reducing agents: Potential reducible loci of ferrylmyoglobin. Free Radical Biology and Medicine, 13, 449–454.
Arduini, A., Eddy, L., & Hochstein, P. (1990). Detection of ferryl myoglobin in the isolated ischemic rat heart. Free Radical Biology and Medicine, 9, 511–513.
Brodie, B.B., Reid, W.D., Cho, A.K., Sipes, I.G., Krishna, G., & Gillette, J.R. (1971). Possible mechanism of liver necrosis caused by aromatic organic compounds. Proc Natl Acad Sci USA, 68, 160–164.
Bryant, M.S., Skipper, P.L., Tannenbaum, S.R., & Maclure, M. (1987). Hemoglobin adducts of 4-aminobiphenyl in smokers and nonsmokers. Cancer Research, 47, 602–608.
Catalano, C.E., Choe, Y.S., & Ortiz de Montellano, P.R. (1989). Reactions of the protein radical in peroxidetreated myoglobin: Formation of a heme-protein cross-link. Journal of Biological Chemistry, 264, 10534–10541.
Galaris, D., Cadenas, E., & Hochstein, P. (1989). Redox cycling of myoglobin and ascorbate: A potential protective mechanism against oxidative reperfusion injury in muscle. Arch Biochem Biophys, 273, 497–504.
Gorelick, N.J., Hutchins, D.A., Tannenbaum, S.R., & Wogan, G.N. (1989). Formation of DNA and hemoglobin adducts of fluoranthene after single and multiple exposures. Carcinogenesis, 10, 1579–1587.
Halpert, J. (1982). Further studies of the suicide inactivation of purified rat liver cytochrome p-450 by chloramphenicol. Mol Pharmacol, 21, 166–172.
Halpert, J., Miller, N.E., & Gorsky, L.D. (1985). On the mechanism of the inactivation of the major phenobarbital-inducible isozyme of rat liver cytochrome P-450 by chloramphenicol. Journal of Biological Chemistry, 260, 8397–8403.
Halpert, J.R. & Stevens, J.C. (1991). Cytochrome P-450 as a target of biological reactive intermediates. Adv Exp Med Biol, 283, 105–109.
Haugen, D.A. (1989). Charge-shift strategy for isolation of hemoglobin-carcinogen adducts formed at the β93 cysteine sulfhydryl groups. Chemical Research in Toxicology, 2, 379–385.
Hinson, J.A. & Roberts, D.W. (1992). Role of covalent and noncovalent interactions in cell toxicity: effects on proteins. Annu Rev Pharmacol Toxicol, 32, 471–510.
Kindt, J.T., Woods, A., Martin, B.M., Cotter, R.J., & Osawa, Y. (1992). Covalent alteration of the prosthetic heme of human hemoglobin by BrCCl3: Cross-linking of heme to cysteine residue 93. Journal of Biological Chemistry, 267, 8739–8743.
McMillan, K., Bredt, D.S., Hirsch, D.J., Snyder, S.H., Clark, J.E., & Masters, B.S.S. (1992). Cloned, expressed rat cerebellar nitric oxide synthase contains stoichiometric amounts of heme, which binds carbon monoxide. Proc Natl Acad Sci USA, 89, 11141–11145.
Olken, N.M., Osawa, Y., & Marietta, M.A. (1994). Characterization of the inactivation of nitric oxide synthase by NG-methyl-L-arginine: evidence for protein modification and heme loss. Biochemistry, In press.
Ortiz de Montellano, P.R. (1990). Free radical modification of prosthetic heme groups. Pharmacol. Then, 48, 95–120.
Ortiz de Montellano, P.R. & Correia, M.A. (1983). Suicidal destruction of cytochrome P-450 during oxidative drug metabolism. Annu Rev Pharmacol Toxicol, 23, 481–503.
Osawa, Y, Fellows, C., Meyer, CM., Woods, A., Castoro, J.A., Cotter, R.J., Wilkins, C, & Highet, R.J. (1994). Structure of the novel heme adduct formed during the reaction of human hemoglobin with BrCCl3 in red cell lysates. Journal of Biological Chemistry, 269, 15481–15487.
Osawa, Y, Darbyshire, J.F., Meyer, CM., & Alayash, A.I. (1993). Differential susceptibilities of the prosthetic heme of hemoglobin-based red cell substitutes. Biochem Pharmacol, 12, 2299–2305.
Osawa, Y, Darbyshire, J.F., Steinbach, P.J., & Brooks, B.R. (1993). Metabolism-based transformation of myoglobin to an oxidase by BrCCl3 and molecular modeling of the oxidase form. Journal of Biological Chemistry. 268, 2953–2959.
Osawa, Y & Davila, J.C. (1993). Phencyclidine, a psychotomimetic agent and drug of abuse, is a suicide inhibitor of brain nitric oxide synthase. Biochem Biophys Res Commun, 194, 1435–1439.
Osawa, Y., Davila, J.C, Meyer, CM. & Nakatsuka, M. (1994). Mechanism based inactivation of nitric oxide synthase, a P450-like enzyme, by xenobiotics. In M.C Lechner (Ed.). Cytochrome P-450: biochemistry, biophysics, and molecular biology pp. 459–462. John Libbey Eurotext, Paris.
Osawa, Y, Fellows, C & Highet, R.J. (1992). Use of stable and radioactive isotopes to identify reactive metabolites and target macromolecules associated with toxicities of halogenated hydrocarbons. In E. Buncel & G.W. Kabalka (Eds.). Synthesis and application of isotopically labelled compounds 1991. proceedings of the fourth international symposium. Toronto, Canada pp. 415–420. Elsevier Science, Amsterdam.
Osawa, Y, Highet, R. J., Bax, A., & Pohl, L.R. (1991). Characterization by NMR of the heme-myoglobin adduct formed during the reductive metabolism of BrCCl3: Covalent bonding of the proximal histidine to the ring I vinyl group. Journal of Biological Chemistry, 266, 3208–3214.
Osawa, Y & Korzekwa, K. (1991). Oxidative modification by low levels of HOOH can transform myoglobin into an oxidase. Proc Natl Acad Sci USA, 88, 7081–7085.
Osawa, Y & Pohl, L.R. (1989). Covalent bonding of the prosthetic heme to protein: A potential mechanism for the suicide inactivation or activation of hemoproteins. Chemical Research in Toxicology. 2, 131–141.
Rachmilewitz, E.A. (1974). Denaturation of the normal and abnormal hemoglobin molecule. Seminars in Hematology, 11, 441–462.
Roberts, E.S., Hopkins, N.E., Zaluzec, E.J., Gage, D.A., Alworth, W.L., & Hollenberg, P.F. (1994). Identification of active-site peptides from 3H-labeled 2-ethynylnaphthalene-inactivated P450 2B1 and 2B4 using amino acid sequencing and mass spectrometry. Biochemistry, 33, 3766–3771.
Roberts, E.S., Hopkins, N.E., Alworth, W.L., & Hollenberg, P.F. (1993). Mechanism-based inactivation of cytochrome P450 2B1 by 2-ethynylnaphthalene: Identification of an active-site peptide. Chemical Research in Toxicology, 6, 470–479.
Stuehr, D.J. & Ikeda-Saito, M. (1992). Spectral characterization of brain and macrophage nitric oxide synthases. Journal of Biological Chemistry, 267, 20547–20550.
Tew, D. & Ortiz de Montellano, P.R. (1988). The myoglobin protein radical: Coupling of Tyr-103 to Tyr-151 in the H2O2-mediated cross-linking of sperm whale myoglobin. Journal of Biological Chemistry, 263, 17880–17886.
White, K.A. & Marietta, M.A. (1992). Nitric oxide synthase is a cytochrome P-450 type hemoprotein. Biochemistry, 31, 6627–6631.
Winslow, R.M. (1992). Hemoglobin-based red cell substitutes. The Johns Hopkins University Press, Baltimore.
Winterbourn, C.C. (1990). Oxidative denaturation in congenital hemolytic anemias: The unstable hemoglobins. Seminars in Hematology, 27, 41–50.
Yao, K., Falick, A.M., Patel, N., & Correia, M.A. (1993). Cumene hydroperoxide-mediated inactivation of cytochrome P450 2B1. Identification of an active site heme-modified peptide. Journal of Biological Chemistry, 268, 59–65.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1996 Springer Science+Business Media New York
About this chapter
Cite this chapter
Osawa, Y., Nakatsuka, K., Williams, M.S., Kindt, J.T., Nakatsuka, M. (1996). Reactions of Reactive Metabolites with Hemoproteins—Toxicological Implications. In: Snyder, R., et al. Biological Reactive Intermediates V. Advances in Experimental Medicine and Biology, vol 387. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-9480-9_6
Download citation
DOI: https://doi.org/10.1007/978-1-4757-9480-9_6
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4757-9482-3
Online ISBN: 978-1-4757-9480-9
eBook Packages: Springer Book Archive