Abstract
It has been known for many years that chronic exposure to benzene leads to bone marrow depression and aplastic anemia and in recent years it has become apparent that benzene can also be leukemogenic (Snyder, 1984). Benzene-induced bone marrow depression is caused by one or more metabolites of benzene (Snyder, et al., 1981). Cytochrane P-450 mediates the first step in benzene metabolism (Gonasun et al., 1973). The initial metabolite formed in the liver is thought to be benzene oxide (Jerina and Daly, 1974) which rearranges to form phenol. Johansson and Ingelmann-Sundberg (1983) suggested that benzene hydroxylation may occur as a result of hydroxyl radical formation during the partially uncoupled mixed function oxidase-mediated metabolism of benzene in which hydrogen peroxide is generated. Nevertheless, it is clear that the major metabolite of benzene., in vivo (Parke and Williams, 1953) and in vitro (Gonasun et al., 1973) is phenol. Because phenol, can be further hydroxylated it is both a product and a substrate in this system. The metabolism of a substrate, either in vivo or in vitro is in part controlled by the concentration at which it encounters the enzyme. In the metabolism of xenoblotic compounds another controlling factor is the type of cytochrome P-450 which metabolizes the compound and hence the importance of enzyme induction. The concentration of an intermediary metabolite such as phenol is a product of the rate at which it is produced and the rate of further metabolism. The issue can be further complicated if both the initial substrate and its metabolite undergo similar reactions and the two compete at the active site of the enzyme. Given this model, we report on some aspects of the metabolism of benzene and phenol.
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References
Andrews, L.S., Lee, E.W., Witmer, C.M., Kocsis, J.J., and Snyder, R. (1977). Effects of toluene on metabolism, disposition, and hematopoietic toxicity of (3H) benzene. Biochem. Pharmacol. 26: 293–300.
Andrews, L.S., Sasame, H.A., and Gillette, J.R. (1979). 3H-Benzene metabolism in rabbit bone marrow Life Sciences 25, 567–572.
Cooper, D.Y., Levin, S., Narasimhulu, S., and Rosenthal, O. (1965). Photochemical action spectrum of the terminal oxidase of mixed function oxidase systems. Science 147, 400–402.
Cooper, D.Y., Schleyer, H., Rosenthal, O., Levin, S., Lu, A.Y., Kuntzman, R., and Conney, A.H. (1977). Inhibition by CO of hepatic benzo[a]pyrene hydroxylation and Its reversal by monochromatic Iight. Fur. J. Biochem. 74, 69–75.
Cooper, D.Y., Schleyer, H., Leviln, S., Eisenhardt, R.H., Novack, B., and Rosenthal, O. (1979). The reevaluation of cytochrane p-450 as the terminal oxidase in hepatic microsomal mixed function oxidase catalyzed reactions Drug Metab. Rev. 10, 153–185.
Gilmour, S. and Snyder, R. (1983a). Metabolism of benzene and phenol in rat liver microsomes. Fed. Proc. 42, 1136.
Gilmour S. and Snyder, R. (1983b). Similarities in the microsomal metabolism of benzene and its metabolite phenol. The pharmacologist 25, 210.
Golmer, L., Graf, H, and Ullrich, V. (1984). Characterization of the benzene monooxygenase in rabbit bone marrow. Biochem. Pharmacol. 33, 3597–3602.
Gonasun, L.M., Witmer, C.M., Kocsis, J.J., and Snyder, R. (1973). Benzene metabolism in mouse liver microsomes. Toxicol. Appl. Pharmacol. 26, 398–406.
Greenlee, W.F., Chism, J.P., and Rickert, D.E. (1981a). A novel method for the separation and quantitation of benzene metabolites using high pressure liquid chromatography Anal. Biochem. 112, 367–370.
Greenlee, W.F., Sun, J.S. and Bus, J.S. (1981b). A proposed mechanism of benzene toxicity: Formation of reactive intermediates from polyphenol metabolites. Toxicol. Appl. Pharmacol.59, 187–195.
Ingelman-Sundberg, M. and Hagbjork, A.L. (1982). On the significance of the cytochrome P-450-dependent hydroxyl radical-mediated oxygenation mechanism. enobiotica 12, 673–686.
Jerina, D. and Daly, J.W. (1974). Arene oxides: A new aspect of drug metabolism, Science, 185, 573–82.
Johansson, I. and Ingelman-Sundberg, M. (1983). Hydroxyl radical-mediated, cytochrome P-450-dependent metabolic activation of benzene in microsomes and reconstituted enzyme systems from rabbit liver. J. Biol. Chem. 258, 7311–7316.
Lunte, S.M. and Kissenger, P.T. (1983). Detection and identification of sulfhydryl conjugates of p-benzoquinone in microsomal incubations of benzene and phenol. Chem.-Biol. Interactions 47, 195–212.
Omura, T. and Sato, R. (1964). The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J. Biol. Chem. 239, 2370–2378.
Parke, D.V. and Williams, R.T. (1953). Studies in detoxication. The metabolism of benzene containing 14C benzene. Riochem. J. 54, 231–238.
Post, G. and Snyder, R. (1983). Effects of enzyme induction on microsomai benzene metabolism. J. Toxicol. Environ. Health 11, 811–825.
Hemmer, H., Schenkman, J.B., Estabrook, R.W., Sasame, H., Gillette, J.R., Narasimhulu, S., Cooper, D.Y. and Rosenthal, O. (1966). Drug interaction with hepatic microsomal cytochrome. Mol. Pharmacol. 2, 187–190.
Rosenthal, O. and Cooper, D.Y. (1967) Methods of determining the photochemical action spectrum. In Methods of Enzymology, Vol. X, R.W. Estabrook and M.E. Pullman, eds., Colowick and Kaplan, series eds., pp. 616–628, Academic press, New York.
Rushmore, T., Snyder, R., and Kalf, G.F. (1984). Covalent binding of benzene and its metabolites to DNA in rabbit bone marrow mitochondria In vitro. çhem.-Biol. Interactions 49, 133–154.
Saito, F., Kocsis, J.J., and Snyder, R. (1973). Effect of benzene on hepatic metabolism and uitrastructure. Toxicol. Appl. Pharmacol. 26, 209–217.
Sawahata, T. and Neal, R.A. (1983). Biotransformation of phenol to hydroquinone and catechol by rat liver microsomes. Mol. Pharmaco1. 23, 453–460.
Schenkman, J.B. (1970). Studies on the nature of the Type I and Type II spectral changes in liver microsomes. Biochemistry 9, 2081–2091.
Schenkman, J.B., Hemmer, H., and Estabrook, R.W. (1967). Spectral studies of drug interaction with hepatic microsomal cytochrome. Mol. Pharmacol. 3, 113–123.
Smart, R.C. and Zannoni, V.G. (1985). Effect of ascorbate on covalent binding of benzene and phenol metabolites to isolated tissue preparation Toxicol. Appl. Pharmacol. 77, 334–343.
Snyder, R., Longacre, S.L., Witmer, C.M., Kocsis, J.J., Andrews, L.S., and Lee, E.W. (1981). Biochemical toxicology of benzene. In: Reviews in Biochemical Toxicolog.X, Elsevier/North Holland Publishing Co., New York, New York, 3: 123–53.
Snyder, R. (1984). The benzene problem in historical perspective. Fund. Appl. Toxicol. 4, 692–699.
Tunek, A., Platt, K.L., Przyblyski, M. and Oesch, F. (1980). Multi-step metabolic activation of benzene. Effect of superoxide dismutase on covalent binding to microsomal macromolecules, and indentification of glutathione conjugates using high pressure liquid chromatography and field desorption mass spectrometry. Chem.-Blol. Interactions 331, 1–7.
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© 1986 Plenum Press, New York
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Gilmour, S.K., Kalf, G.F., Snyder, R. (1986). Comparison of the Metabolism of Benzene and Its Metabolite Phenol in Rat Liver Microsomes. In: Kocsis, J.J., Jollow, D.J., Witmer, C.M., Nelson, J.O., Snyder, R. (eds) Biological Reactive Intermediates III. Advances in Experimental Medicine and Biology, vol 197. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5134-4_19
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DOI: https://doi.org/10.1007/978-1-4684-5134-4_19
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