Effects of Hydroxyl Group Numbers on the B-Ring of 5,7-Dihydroxyflavones on the Differential Inhibition of Human CYP 1A and CYP1B1 Enzymes

  • Kim Hyun-Jung (School of Life Sciences and Biotechnology, Korea University) ;
  • Lee Sang Bum (School of Life Sciences and Biotechnology, Korea University) ;
  • Park Song-Kyu (Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim Hwan Mook (Korea Research Institute of Bioscience and Biotechnology) ;
  • Park Young In (School of Life Sciences and Biotechnology, Korea University) ;
  • Dong Mi-Sook (School of Life Sciences and Biotechnology, Korea University)
  • Published : 2005.10.01

Abstract

Flavonoids are polyphenols composed of two aromatic rings (A, B) and a heterocyclic ring (C). In order to determine the effects of the number of hydroxyl groups in the B-ring of the flavonoids on human cytochrome P450 (CYP) 1 family enzymes, we evaluated the inhibition of CYP1A-dependent 7-ethoxyresorufin O-deethylation activity by chrysin, apigenin and luteolin, using bacterial membranes that co-express human CYP1A1, CYP1A2, or CYP1B1 with human NADPH-cytochrome P450 reductase. Chrysin, which possesses no hydroxyl groups in its B-ring, exhibited the most pronounced inhibitory effects on CYP1A2-dependent EROD activity, followed by apigenin and luteolin. On the contrary, CYP1A1-mediated EROD activity was most potently inhibited by luteolin, which is characterized by two hydroxyl groups in its B-ring, followed by apigenin and chrysin. However, all of the 5,7-dihydroxyflavones were determined to similarly inhibit CYP1B1 activity. Chrysin, apigenin, and luteolin exhibited a mixed-type mode of inhibition with regard to CYP1A2, CYP1B1, and CYP1A1, with apparent Ki values of 2.4, 0.5, and 2.0 ${\mu}M$, respectively. These findings suggested that the number of hydroxyl groups in the B-ring of 5,7-dihydroxyflavone might have some influence on the degree to which CYP1A enzymes were inhibited, but not on the degree to which CYP1B1 enzymes were inhibited.

Keywords

References

  1. Breinholt, V. M., Offord, E. A., Brouwer, C., Nielsen, S. E., Brosen, K., and Friedberg, T., In vitro investigation of cytochrome P450-mediated metabolism of dietary flavonoids. Food Chem. Toxicol., 40, 609-616 (2002) https://doi.org/10.1016/S0278-6915(01)00125-9
  2. Dai, R., Zhai, S., Wei, X., Pincus, M. R., Vestal, R. E., and Friedman, F. K., Inhibition of human cytochrome P4501A2 by f1avones: a molecular modeling study. J. Protein Chem., 17, 643-650 (1998) https://doi.org/10.1007/BF02780965
  3. Dong, M.-S., Chang, S. K., Kim, H. J., Gillam, E. M. J., Guengerich, F. P., and Park, Y. I., Inhibition of 7-alkoxyresorufin O-dealkylation activities of recombinant human CYP1A1 and CYP1B1 by resveratrol. Environ. Mutagen Carcinogens, 22, 169-174 (2002)
  4. Doostdar, H., Burke, M. D., and Mayer, R. T., Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1. Toxicology, 144, 31-38 (2000) https://doi.org/10.1016/S0300-483X(99)00215-2
  5. Frank, A. A., Cooney, R. V., Custer, L. J., Mordan, L. J., and Tanaka, Y., Inhibition of neoplastic transformation and bioavailability of dietary flavonoid agents. Adv. Exp. Med. Biol., 439, 237-248 (1998)
  6. Gonzalez, F. J. and Gelboin, H. V., Role of human cytochrome P450 in the metabolic activation of chemical carcinogens and toxins. Drug Metab. Rev., 26, 165-183 (1994) https://doi.org/10.3109/03602539409029789
  7. Guengerich, F. P., Human cytochrome P450 enzymes. In Cytochrome P450: Structure, Mechanism and Biochemistry, 2nd edition, P. R. Ortiz de Montellano (Eds.). Plenum Press, New York, pp. 473-535, (1995)
  8. Guengerich, F. P. and Shimada, T., Activation of procarcinogens by human cytochrome P450 enzymes. Mutat. Res., 400, 201-213 (1998) https://doi.org/10.1016/S0027-5107(98)00037-2
  9. Hodek, P., Trefil, P., and Stiborova, M., Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450. Chemico-Biological lnteractions, 139, 1-21 (2002) https://doi.org/10.1016/S0009-2797(01)00285-X
  10. Kanazawa, K., Yamashita, T., Ashida, H., and Danno, G., Antimutagenicity of f1avones and flavonols to heterocyclic amines by specific and strong inhibition of the cytochrome P450 1A family. Biosci. Biotech. Biochem., 62, 970-977 (1998) https://doi.org/10.1271/bbb.62.970
  11. Kang, I. H., Kim, H. J., Oh, H., Park, Y. I., and Dong, M.-S., Biphasic effects of the f1avonoids quercetin and naringenin on the metabolic activation of 2-arnino-3,5-dimethylimidazo 4,5-f quinoline by Salmonella typhimurium TA1538 coexpressing human cytochrome P450 1A2, NADPH-cyto-chrome P450 reductase and cytochrome $b_5$. Mutat. Res., 545, 37-47 (2004) https://doi.org/10.1016/j.mrfmmm.2003.08.002
  12. Lautraite, S., Musonda, A. C., Doehmer, J., Edwards, G.O., and Chipman, J. K., Flavonoids inhibit qenetic toxicity produced by carcinogens in cells expressinq CYP1A2 and CYP1A1. Mutagenesis, 17, 45-53 (2002) https://doi.org/10.1093/mutage/17.1.45
  13. Lee, H., Yeom, H., Kim, Y. G., Yoon, C. N., Jin, C., Choi, J. S., Kim, B. R., and Kim, D. H., Structure-related inhibition of human hepatic caffeine N3-dernethylation by naturally occurring flavonoids. Biochem. Pharm., 55, 1369-1375 (1998) https://doi.org/10.1016/S0006-2952(97)00644-8
  14. Moon, J. Y., Lee, D. W., and Park, K. H., Inhibition of 7-ethoxycoumarin O-deethylase activity in rat liver microsomes by naturally occurring flavonoids: structure-activity relationships. Xenobiotica, 28, 117-126 (1998) https://doi.org/10.1080/004982598239623
  15. Omura, T. and Sato, R., The carbon monoxide-binding pigment of liver microsome. I. Evidence for its hemoprotein nature. J. Biol. Chem., 239, 2370-2378 (1964)
  16. Parikh, A., Gillam, E. M. J., and Guengerich, F. P., Drug meta-bolism by Escherichia coli expressing human cytochromes P450. Nat. Biotechnol., 15, 784-788 (1997) https://doi.org/10.1038/nbt0897-784
  17. Pietta, P. G., Flavonoids as antioxidants. J. Nat. Product, 63, 1035-1042 (2000) https://doi.org/10.1021/np9904509
  18. Rendic, S. and Di Carlo, F. J., Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers and inhibitors. Drug Metab. Rev., 29, 413-580 (1997) https://doi.org/10.3109/03602539709037591
  19. Ross, J. A. and Kasum, C. M., Dietary f1avonoids: bioavailability, metabolic effects and safety. Annu. Rev. Nutr., 22, 19-34 (2002) https://doi.org/10.1146/annurev.nutr.22.111401.144957
  20. Shimada, T., Wunsch, R. M., Hanna, I. H., Sutter, T. R., Guengerich, F. P., and Gillam, E. M. J., Recombinant human cytochrome CYP1B1 expression in Escherichia coli. Arch. Biochem. Biophys., 357, 111-120 (1998) https://doi.org/10.1006/abbi.1998.0808
  21. So, F. V., Guthrie, N., Chambers, A. F., Moussa, M., and Carroll, K. K., Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr. Cancer, 26, 167-181 (1996) https://doi.org/10.1080/01635589609514473
  22. Takahashi, E., Fujita, K., Kamataki, T., Arimoto-Kobayashi, S., Okamoto, K., and Negishi, T., Inhibition of human cytochrome P450 1B1, 1A1, and 1A2 by antigenotoxic compounds purpurin and alizarin. Mutat. Res., 508, 147-156 (2002) https://doi.org/10.1016/S0027-5107(02)00212-9
  23. Tanaka, T., Makita, H., Ohnishi, M., Mori, H., Satoh, K., Hara, A., Sumida, T., Fukutani, K., Tanaka, T., and Ogawa, H., Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis in rats by flavonoids diosmin and hesperedin, each alone and in combination. Cancer Res., 57, 246-252 (1997)
  24. Yasukochi, Y. and Masters, B. S. S., Some properties of a detergent-solubilized NADPH-cytochrome c (cytochrome P450): Reductase purified by biospecific affinity chromatography. J. Biol. Chem., 251, 5337-5344 (1976)
  25. Zhai, S., Dai, R., Friedman, F. K., and Vestal, R. E., Comparative inhibition of human cytochromes P450 1A1 and 1A2 by flavonoids. Drug Metab. Dispos., 26, 989-992 (1998)
  26. Kim, J. Y., Lee, S., Kim, D. H., Kim, B. R., Park, R., and Lee, B. M., Effects of f1avonoids isolated from Scutellariae radix on cytochrome P-450 activities in human liver microsomes. J. Toxicol. Environ. Health, 65, 373-381 (2002) https://doi.org/10.1080/15287390252808046