Abstract
In order to understand the mechanism of action of flavonoids on the drug metabolizing enzyme, cytochrome P4501A1, this study was undertaken to examine the effect of chrysin, morin, myricetin and aminopyrine on the activities of ethoxyresorufin O-deethylase and benzo(α) pyrene hydroxylase in the liver. In the isolated perfused rat liver that was pretreated with 3-methylcholanthrene (3MC), chrysin, morin, myricetin and aminopyrine inhibited the activity of ethoxyresorufin O-deethylase with concentration dependent manner. The isolated liver perfusion with chrysin, morin, myricetin and aminopyrine showed inhibition on the induction of ethoxyresorufin O-deethylase by 3MC. And also, in mouse liver hepa I cells, 3MC-stimulated the benzo(α)pyrene hydroxylase activity which was inhibited by chrysin, morin, myricetin and aminopyrine. These results strongly suggested that hydoxylated flavonoids interfered not only the induction of cytochrome P450IA1 enzymes by 3MC but also the interaction of substrates and enzyme.
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References Cited
Buening, M. K., Chang, R. L., Huang, Mou-Tuan, Forther, J. G., Wood, A. W. and Conney, A. H., Activation and inhibition of benzo(α)pyrene and aflatoxin B1 metabolism in human liver microsomes by naturally occuring flavonoids.Cancer Research, 41, 67–72 (1981).
Canivenc-Lavier, M. C., Bentejac, M., Miller, M. L., Leclerc, J., Siess, M. H., Latruffe, N. and Suschetet, M. Differential effects of nonhydroxylated flavonoids as inducers of cytochrome P450 1A and IIB isozymes in rat liver.Toxicol. Appl. Pharmacol., 136, 348–53 (1996).
Cody, V., Middleform, E., Itaborne, J. B. and Beretz, A.,Plants Flavonoids in biology and medicine II: Biochemical cellular and Medicinal Properties. Alan R. Liss, Inc., New York, 1988.
Das, N. P.,Flavonoids in Biology and Medicine III: structure and activity. National University of Singapore, Singapore, 1989.
Denison, M. S., Fisher, J. M. and Whitlock, J. P., The DNA recognition site for the dioxin-Ah receptor complex.J. Biol. Chem., 85, 2528–2532 (1988).
Farkas, L., Garbor, M. and Kally, F.,Flavonoids and Bioflavonoids: physiology and pharmacology. Akademiai Kiado, Budapast 1986.
Foldes, R. L., Hines, R. N., Ho, Kai-Ling, Shen, Mei-Ling, Nagel, K. B. and Bresnic, E., 3-Methyl-cholanthrene-induced expression of the cytochrome P-450c gene.Archives of Biochemistry and Biophysics, 239, 137–146 (1985).
Fujino, T., West, D., Park, S. S. and Gelboin, H. V., Monoclonal antibody-directed phenotyping of cytochrome P-450 dependent aryl hydrocarbon hydroxylase and 7-ethoxycoumarin deethylase in mammalian tissues.J. Biol, Chem., 259, 9044–9050 (1984).
Guengerich, F. P., Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy.Cancer Research, 48, 2946–2954 (1988).
Hapgood, J., Cuthill, S., Denis, M., Poellinger, L. and Gustafsson, J. A., Specific protein-DNA interaction at a xenobiotic-responsive element: Copurification of dioxin receptor and DNA-binding activity.Proc. Natl, Acad. Sci., 86, 60–64 (1989).
Hines, R. N., Mathis, J. M. and Jacob, C. S., Identification of multiple regulatory elements on the human cytochrome P450IA1 gene.Carcinogenesis, 9, 1599–1605 (1988).
Okey, A. B., Bondy, G. P., Mason, M. E., Nebert, D. W., Forster-Gibson, C. J., Muncan, J. and Dufresne, M. J., Temperature-dependent cytosol-to-nucleus translocation of the Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin in continuous cell culture lines.J. Biol, Chem., 255, 11415–11422 (1980).
Selway, J. W. T.Plant flavonoids in biology and medicine: Biochemical, pharmacological and structure-activity relationships, Cody, V., Middleton, E. and Harbone, J. B., (Eds.), Alan R. Liss, Inc. New York, pp. 521–536, 1986.
Sousa, R. L., and Marletta, M. A., Inhibition of cytochrome P-450 activity in rat liver microsomes by the naturally occurring flavonoid, quercetin.Arch. Biochem. Biophys., 240, 345–357 (1985).
Teija O., Sirkku S., Kirsti H., Ari, H. and Kai, O.L., Pretranslational induction of cytochrome P450IA enzymes by β-Naphthoflavone and 3-Methylcholanthrene occurs in different liver zones.Biochem. Pharmacol., 48, 2189–2197 (1994).
Tinberlake, C. F. and Henry, B. S. Flavonoids and food.Endeavour, 10, 31–37 (1986).
Whitlock, J. P. Jr. The regulation of cytochrome P-450 gene expression.Ann. Rev. Pharmacol. Toxicol., 26, 333–369 (1986).
Yao, E. F. and Denison, M. S., DNA sequence determinants for binding of transformed Ah receptor to a dioxin-responsive enhancer.Biochemistry, 31, 5060–5067 (1992).
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Han, S.H., Sheen, Y.Y. Effects of hydroxylated flavonoids on the ethoxyresorufin O-deethylase and benzo(α)pyrene hydroxylase. Arch. Pharm. Res. 19, 514–519 (1996). https://doi.org/10.1007/BF02986021
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DOI: https://doi.org/10.1007/BF02986021