Advertisement

Effects of hydroxyl group numbers on the B-ring of 5,7-dihydroxyflavones on the differential inhibition of human CYP 1A and CYP1B1 enzymes

  • Hyun-Jung Kim
  • Sang Bum Lee
  • Song-Kyu Park
  • Hwan Mook Kim
  • Young In Park
  • Mi-Sook Dong
Articles Drug Design

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-ethoxyresorufinO-deethylation activity by chrysin, apigenin and luteolin, using bacterial membrances 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 contray, 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 mixedtype mode of inhibition with regard to CYP1A2, CYP1B1, and CYP1A1, with apparent Ki values of 2.4, 0.5, and 2.0 μM, 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.

Key words

CYP1 enzymes EthoxyresorufinO-deethylase Chrysin Apigenin Luteolin 

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).PubMedCrossRefGoogle Scholar
  2. Dai, R., Zhai, S., Wei, X., Pincus, M. R., Vestal, R. E., and Friedman, F. K., Inhibition of human cytochrome P4501A2 by flavones: a molecular modeling study.J. Protein Chem., 17, 643–650 (1998).PubMedCrossRefGoogle Scholar
  3. Dong, M.-S., Chang, S. K., Kim, H. J., Gillam, E. M. J., Guengerich, F. P., and Park, Y. I., Inhibition of 7-alkoxyresorufinO-dealkylation activities of recombinant human CYP1A1 and CYP1B1 by resveratrol.Environ. Mutagen Carcinogens, 22, 169–174 (2002).Google Scholar
  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).PubMedCrossRefGoogle Scholar
  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).Google Scholar
  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).PubMedCrossRefGoogle Scholar
  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).Google Scholar
  8. Guengerich, F. P. and Shimada, T., Activation of procarcinogens by human cytochrome P450 enzymes.Mutat. Res., 400, 201–213 (1998).PubMedGoogle Scholar
  9. Hodek, P., Trefil, P., and Stiborova, M., Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450.Chemico-Biological Interactions, 139, 1–21 (2002).PubMedCrossRefGoogle Scholar
  10. Kanazawa, K., Yamashita, T., Ashida, H., and Danno, G., Antimutagenicity of flavones and flavonols to heterocyclic amines by specific and strong inhibition of the cytochrome P450 1A family.Biosci. Biotech. Biochem., 62, 970–977 (1998).CrossRefGoogle Scholar
  11. Kang, I. H., Kim, H. J., Oh, H., Park, Y. I., and Dong, M.-S., Biphasic effects of the flavonoids quercetin and naringenin on the metabolic activation of 2-amino-3,5-dimethylimidazo-[4,5-f]quinoline bySalmonella typhimurium TA1538 coexpressing human cytochrome P450 1A2, NADPH-cytochrome P450 reductase and cytochrome b5.Mutat. Res., 545, 37–47 (2004).PubMedGoogle Scholar
  12. Lautraite, S., Musonda, A. C., Doehmer, J., Edwards, G. O., and Chipman, J. K., Flavonoids inhibit genetic toxicity produced by carcinogens in cells expressing CYP1A2 and CYP1A1.Mutagenesis, 17, 45–53 (2002).PubMedCrossRefGoogle Scholar
  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 caffeineN 3-demethylation by naturally occurring flavonoids.Biochem. Pharm., 55, 1369–1375. (1998).PubMedCrossRefGoogle Scholar
  14. Moon, J. Y., Lee, D. W., and Park, K. H., Inhibition of 7-ethoxycoumarinO-deethylase activity in rat liver microsomes by naturally occurring flavonoids: structure-activity relationships.Xenobiotica, 28, 117–126 (1998).PubMedCrossRefGoogle Scholar
  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).PubMedGoogle Scholar
  16. Parikh, A., Gillam, E. M. J., and Guengerich, F. P., Drug metabolism byEscherichia coli expressing human cytochromes P450.Nat. Biotechnol., 15, 784–788 (1997).PubMedCrossRefGoogle Scholar
  17. Pietta, P. G., Flavonoids as antioxidants.J. Nat. Product, 63, 1035–1042 (2000).CrossRefGoogle Scholar
  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).PubMedCrossRefGoogle Scholar
  19. Ross, J. A. and Kasum, C. M., Dietary flavonoids: bioavailability, metabolic effects and safety.Annu. Rev. Nutr., 22, 19–34 (2002).PubMedCrossRefGoogle Scholar
  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 inEscherichia coli.Arch. Biochem. Biophys., 357, 111–120 (1998).PubMedCrossRefGoogle Scholar
  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).PubMedCrossRefGoogle Scholar
  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).PubMedGoogle Scholar
  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).PubMedGoogle Scholar
  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).PubMedGoogle Scholar
  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).PubMedGoogle Scholar
  26. Kim, J. Y., Lee, S., Kim, D. H., Kim, B. R., Park, R., and Lee, B. M., Effects of flavonoids isolated from Scutellariae radix on cytochrome P-450 activities in human liver microsomes.J. Toxicol. Environ. Health, 65, 373–381 (2002).CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2005

Authors and Affiliations

  • Hyun-Jung Kim
    • 1
  • Sang Bum Lee
    • 1
  • Song-Kyu Park
    • 2
  • Hwan Mook Kim
    • 2
  • Young In Park
    • 1
  • Mi-Sook Dong
    • 1
  1. 1.School of Life Sciences and BiotechnologyKorea UniversitySeoulKorea
  2. 2.Korea Research Institute of Bioscience and BiotechnologyDaejeonKorea

Personalised recommendations