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Tissue distribution in mice and metabolism in murine and human liver of apigenin and tricin, flavones with putative cancer chemopreventive properties

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Abstract

Purpose

The flavones apigenin and tricin, which occur in leafy vegetables and rice bran, respectively, possess cancer chemopreventive properties in preclinical rodent models. Their pharmacology is only poorly understood. We compared their tissue levels in mice in vivo and their metabolism in liver fractions in vitro.

Methods

Mice received apigenin or tricin (0.2%) with their diet for 5–7 days, and flavone levels were compared in the plasma, liver and gastrointestinal mucosa using HPLC–UV. Flavone metabolism was investigated in murine and human liver microsomes or cytosol in vitro co-incubated with uridine 5′-diphosphoglucuronic acid or 3′-phosphoadenosine-5′ phosphosulfate. Flavone metabolites were characterized by on-line HPLC–mass spectrometry.

Results

After dietary administration of flavones for 7 days, levels of tricin in plasma, liver and mucosa exceeded those of apigenin by 350, 33 and 100%, respectively. Apigenin was more rapidly glucuronidated than tricin in liver microsomes, whilst tricin underwent swifter sulfonation than apigenin in liver cytosol. For either flavone the rate of glucuronidation was much faster than that of sulfonation. Flavone monoglucuronides and monosulfates were identified as metabolites in microsomal and cytosolic incubations, respectively.

Conclusions

When consumed with the diet in mice tricin seems to be more available than apigenin in blood and tissues. Differences in their glucuronidation may account for their differential availability. Thus tricin may have a pharmacokinetic advantage over apigenin. This type of information may help decide which flavonoids to select for clinical development.

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References

  1. Witte JS, Longnecker P, Bird CL, Lee ER, Frank LHD, Haile RW (1996) Relation of vegetable, fruit and grain consumption to colorectal adenomatous polyps. Am J Epidemiol 144:1015–1025

    PubMed  CAS  Google Scholar 

  2. Gescher A (2004) Polyphenolic phytochemicals versus non-steroidal anti-inflammatory drugs: Which are better cancer chemopreventive agents? J Chemother 16(Suppl 4):3–6

    PubMed  CAS  Google Scholar 

  3. Al-Fayez M, Cai H, Tunstall R, Steward WP, Gescher AJ (2006) Differential modulation of cyclooxygenase-mediated prostaglandin production by the putative cancer chemopreventive flavonoids tricin, apigenin and quercetin. Cancer Chemother Pharmacol 58:816–825

    Article  PubMed  CAS  Google Scholar 

  4. Cai H, Al-Fayez M, Tunstall RG, Platton S, Greaves P, Steward WP, Gescher AJ (2005) The rice bran constituent tricin potently inhibits cyclooxygenase enzymes and interferes with intestinal carcinogenesis in Apc Min mice. Mol Cancer Ther 4:1287–1292

    Article  PubMed  CAS  Google Scholar 

  5. Workman P, Twentyman P, Balkwill F, Balmain A, Chaplin D, Double J, Embleton J, Newell D, Raymond R, Stables J, Stephens T, Wallace J (1998) United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) guidelines for the welfare of animals in experimental neoplasia (2nd edition). Brit J Cancer 77:1–10

    Google Scholar 

  6. Gibson GG, Skett P (eds) (2001) Introduction to drug metabolism, 3rd edn. Nelson Thornes Publishers, Cheltenham

  7. Cai H, Verschoyle RD, Steward WP, Gescher AJ (2003) Determination of the flavone tricin in human plasma by high performance liquid chromatography. J Biomed Chromatogr 17:435–439

    Article  CAS  Google Scholar 

  8. Cai H, Steward WP, Gescher AJ (2005) Determination of the putative cancer chemopreventive flavone tricin in plasma and tissue of mice by HPLC with UV–visible detection. J Biomed Chromatogr 19:518–522

    Article  CAS  Google Scholar 

  9. Cai H, Raynaud D, Steward WP, Gescher AJ (2006) A simple HPLC method for the determination of apigenin in mouse tissue. J Biomed Chromatogr 20:1038–1042

    Article  CAS  Google Scholar 

  10. Li B., Robinson DH., Birt DF (1997) Evaluation of properties of apigenin and [G-3H] apigenin and analytic method development. J Pharm Sci 86:721–725

    Article  PubMed  CAS  Google Scholar 

  11. Mabry TJ, Markham KR, Thomas MB (eds) (1970) The systematic identification of flavonoids. Springer, Berlin Heidelberg New York

  12. Gradolatto A, Canivenc-Lavier MC, Basly JP, Siess MH, Teyssier C (2004) Metabolism of apigenin by rat liver phase I and phase II enzymes and by isolated perfused rat liver. Drug Metab Dispos 32:58–65

    Article  PubMed  CAS  Google Scholar 

  13. Manach C, Donovan JL (2004) Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radic Res 38:771–785

    Article  PubMed  CAS  Google Scholar 

  14. Ross JA, Kasum CM (2002) Dietary flavonoids: bioavailability, metabolic effects and safety. Annu Rev Nutr 22:19–34

    Article  PubMed  CAS  Google Scholar 

  15. Nielsen SE, Dragsted LO (1998) Column-switching high-performance liquid chromatographic assay for determination of apigenin and acacetin in human urine with ultraviolet absorbance detection. J Chromatogr Biomed Appl 713:379–386

    Article  CAS  Google Scholar 

  16. Walle UK, Walle T (2002) Induction of human UDP-glucuronosyltransferase UGT1A1 by flavonoids-structural requirements. Drug Metab Dispos 30:564–569

    Article  PubMed  CAS  Google Scholar 

  17. Czeczot H, Tudek B, Kusztelak J, Szymczyk T, Dobrowolska B, Glinkowska G, Malinowski J, Strzelecka H (1990) Isolation and studies of the mutagenic activity in the Ames test of flavonoids naturally occurring in medical herbs. Mutat Res 240:209–216

    Article  PubMed  CAS  Google Scholar 

  18. Verschoyle RD, Greaves P, Cai H, Borkhardt A, Broggini M, D’Incalci M, Riccio E, Doppalapudi R, Kapetanovic IM, Steward WP, Gescher AJ (2005) Preliminary safety evaluation of the putative cancer chemopreventive agent tricin, a naturally occurring flavone. Cancer Chemother Pharmacol 57:1–6

    Article  PubMed  Google Scholar 

  19. Hudson EA, Dinh PA, Kokubun T, Simmonds M, Gescher AJ (2000) Characterization of potentially chemopreventive phenols in extracts of brown rice which inhibit the growth of human breast and colon cancer cells. Cancer Epidemiol Biomarkers Prev 9:1163–1170

    PubMed  CAS  Google Scholar 

  20. YinYin F, Giuliano AE, Law RE, Van Herle AJ (2001) Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast cells. Anticancer Res 21:413–420

    Google Scholar 

  21. Yoshizumi M, Tsuchiya K, Suzaki Y, Kirima K, Kyaw M, Moon J-H, Terao J, Tamaki T (2002) Quercetin glucuronide prevents VSMC hypertrophy by angiotensin H via the inhibition of JNK and AP-1 signaling pathways. Biochem Biophys Res Commun 293:1458–1465

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by programme grant G0100874 from the Medical Research Council and a “Rapid Access to Preventive Intervention Development” (RAPID) grant from the US National Cancer Institute. The authors thank Ms Delphine Reynaud for help with the HPLC analysis and Dr Izet M Kapetanovic (NCI Div of Cancer Prevention, Bethesda MD) for advice and efficient organization of tricin synthesis and delivery.

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Authors and Affiliations

  1. Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK

    Hong Cai, David J. Boocock, William P. Steward & Andreas J. Gescher

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  1. Hong Cai
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  2. David J. Boocock
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  3. William P. Steward
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  4. Andreas J. Gescher
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Correspondence to Andreas J. Gescher.

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Cai, H., Boocock, D.J., Steward, W.P. et al. Tissue distribution in mice and metabolism in murine and human liver of apigenin and tricin, flavones with putative cancer chemopreventive properties. Cancer Chemother Pharmacol 60, 257–266 (2007). https://doi.org/10.1007/s00280-006-0368-5

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  • DOI: https://doi.org/10.1007/s00280-006-0368-5

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