Bioavailability challenges associated with development of anti-cancer phenolics

Mini-Reviews in Medicinal Chemistry

Volumn 10, Issue 6, 2010, Pages 550-567

  Gao, S ^a   Hu, M ^a  

^a UNIVERSITY OF HOUSTON   (United States)

Author keywords

Bioavailability challenge; Chemoprevention; Chemotherapy; Flavonoids; Phenolic; Polyphenol

Indexed keywords

ANTHOCYANIN; ANTINEOPLASTIC AGENT; AURANTIIN; BAICALIN; CAFFEIC ACID; COUMARIN; DAIDZEIN; DAIDZIN; DELPHINIDIN; ELLAGIC ACID; EQUOL; FLAVONOID; GENISTEIN; GLYCOSIDE; HESPERIDIN; KAEMPFEROL; LUTEOLIN; NARIGENIN; O DESMETHYLANGOLENSIN; PELARGONIDIN; PHENOL DERIVATIVE; PHLOROGLUCINOL DERIVATIVE; POLYPHENOL DERIVATIVE; PUERARIN; QUINONE DERIVATIVE; RESVERATROL; ROSMARINIC ACID; RUTOSIDE; STILBENE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CHEMOTHERAPY; CANCER PREVENTION; DIFFUSION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG MECHANISM; DRUG METABOLISM; DRUG PENETRATION; DRUG SOLUBILITY; DRUG STABILITY; EFFUSION; GLUCURONIDATION; HUMAN; HYDROLYSIS; IN VIVO STUDY; NONHUMAN; SULFATION;

ANIMALS; ANTICARCINOGENIC AGENTS; ANTINEOPLASTIC AGENTS; BIOLOGICAL AVAILABILITY; CLINICAL TRIALS AS TOPIC; FLAVONOIDS; HUMANS; NEOPLASMS; PHENOLS; RATS;

EID: 77953713797     PISSN: 13895575     EISSN: None     Source Type: Journal    
DOI: 10.2174/138955710791384081     Document Type: Article

References (132)

1. Neuhouser, M. L. Dietary flavonoids and cancer risk: evidence from human population studies. Nutr. Cancer, 2004, 50, 1-7.
2. Prasain, J. K.; Barnes, S. Metabolism and bioavailability of flavonoids in chemoprevention: current analytical strategies and future prospectus. Mol. Pharm., 2007, 4, 846-864.
3. Ramos, S. Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. Mol. Nutr. Food Res., 2008, 52, 507-526.
4. Crozier, A.; Jaganath, I. B.; Clifford, M. N. Dietary phenolics: chemistry, bioavailability and effects on health. Nat. Prod. Rep., 2009, 26, 1001-1043.
5. Harnly, J. M.; Bhagwat, S.; Lin, L. Z. Profiling methods for the determination of phenolic compounds in foods and dietary supplements. Anal. Bioanal. Chem., 2007, 389, 47-61.
6. Galati, G.; O'Brien, P. J. Potential toxicity of flavonoids and other dietary phenolics: significance for their chemopreventive and anticancer properties. Free Radic. Biol. Med., 2004, 37, 287-303.
7. Chavez-Santoscoy, R. A.; Gutierrez-Uribe, J. A.; Serna-Saldivar, S. O. Phenolic composition, antioxidant capacity and in vitro cancer cell cytotoxicity of nine prickly pear (Opuntia spp.) juices. Plant Foods Hum. Nutr., 2009, 64, 146-152.
8. Bermudez-Soto, M. J.; Larrosa, M.; Garcia-Cantalejo, J.; Espin, J. C.; Tomas-Barberan, F. A.; Garcia-Conesa, M. T. Transcriptional changes in human Caco-2 colon cancer cells following exposure to a recurrent non-toxic dose of polyphenol-rich chokeberry juice. Genes Nutr. 2007, 2, 111-113.
9. Kundu, J. K.; Na, H. K.; Surh, Y. J. Ginger-derived phenolic substances with cancer preventive and therapeutic potential. Forum. Nutr., 2009, 61, 182-192.
10. Wang, X.; Hao, M. W.; Dong, K.; Lin, F.; Ren, J. H.; Zhang, H. Z. Apoptosis induction effects of EGCG in laryngeal squamous cell carcinoma cells through telomerase repression. Arch. Pharm. Res., 2009, 32, 1263-1269.
11. Ohga, N.; Hida, K.; Hida, Y.; Muraki, C.; Tsuchiya, K.; Matsuda, K.; Ohiro, Y.; Totsuka, Y.; Shindoh, M. Inhibitory effects of epigallocatechin-3 gallate, a polyphenol in green tea, on tumorassociated endothelial cells and endothelial progenitor cells. Cancer Sci., 2009, 100, 1963-1970.
12. Scheckel, K. A.; Degner, S. C.; Romagnolo, D. F. Rosmarinic acid antagonizes activator protein-1-dependent activation of cyclooxygenase-2 expression in human cancer and nonmalignant cell lines. J. Nutr., 2008, 138, 2098-2105.
13. Ahn, M. Y.; Jung, J. H.; Na, Y. J.; Kim, H. S. A natural histone deacetylase inhibitor, Psammaplin A, induces cell cycle arrest and apoptosis in human endometrial cancer cells. Gynecol. Oncol., 2008, 108, 27-33.
14. Skarydova, L.; Zivna, L.; Xiong, G.; Maser, E.; Wsol, V. AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids. Chem. Biol. Interact., 2009, 178, 138-144.
15. Golkar, L.; Ding, X. Z.; Ujiki, M. B.; Salabat, M. R.; Kelly, D. L.; Scholtens, D.; Fought, A. J.; Bentrem, D. J.; Talamonti, M. S.; Bell, R. H.; Adrian, T. E. Resveratrol inhibits pancreatic cancer cell proliferation through transcriptional induction of macrophage inhibitory cytokine-1. J. Surg. Res., 2007, 138, 163-169.
16. Ravindranath, M. H.; Ramasamy, V.; Moon, S.; Ruiz, C.; Muthugounder, S. Differential Growth Suppression of Human Melanoma Cells by Tea (Camellia sinensis) Epicatechins (ECG, EGC and EGCG). Evid. Based Complement Alternat. Med., 2009, 6, 523-530.
17. Gawande, S.; Kale, A.; Kotwal, S.Effect of nutrient mixture and black grapes on the pharmacokinetics of orally administered (-)epigallocatechin-3-gallate from green tea extract: a human study. Phytother. Res., 2008, 22, 802-808.
18. de la Lastra, C. A.; Villegas, I. Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol. Nutr. Food Res., 2005, 49, 405-430.
19. Nunes, T.; Almeida, L.; Rocha, J. F.; Falcao, A.; Fernandes-Lopes, C.; Loureiro, A. I.; Wright, L.; Vaz-da-Silva, M.; Soares-da-Silva, P. Pharmacokinetics of trans-resveratrol following repeated administration in healthy elderly and young subjects. J. Clin. Pharmacol., 2009, 49, 1477-1482.
20. Decker, E. A. Phenolics: prooxidants or antioxidants? Nutr. Rev., 1997, 55, 396-398.
21. Karakaya, S. Bioavailability of phenolic compounds. Crit. Rev. Food Sci. Nutr., 2004, 44, 453-464.
22. Fresco, P.; Borges, F.; Diniz, C.; Marques, M. P. New insights on the anticancer properties of dietary polyphenols. Med. Res. Rev., 2006, 26, 747-766.
23. Spencer, J. P.; Schroeter, H.; Rechner, A. R.; Rice-Evans, C. Bioavailability of flavan-3-ols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo. Antioxid. Redox. Signal., 2001, 3, 1023-1039.
24. McGhie, T. K.; Walton, M. C. The bioavailability and absorption of anthocyanins: towards a better understanding. Mol. Nutr. Food Res., 2007, 51, 702-713
25. Kerns, E. H.; Di. L. In: Drug-like Properties: Concepts, Structure Design and Methods for ADME to Toxicity Optimization. Elsevier Inc: Oxford, 2008, pp. 56-85.
26. Muller, C. E. Prodrug approaches for enhancing the bioavailability of drugs with low solubility. Chem. Biodivers., 2009, 6, 2071-2083.
27. Anderson, A.; Belelli, D.; Bennett, D. J.; Buchanan, K. I.; Casula, A.; Cooke, A.; Feilden, H.; Gemmell, D. K.; Hamilton, N. M.; Hutchinson, E. J.; Lambert, J. J.; Maidment, M. S.; McGuire, R.; McPhail, P.; Miller, S.; Muntoni, A.; Peters, J. A.; Sansbury, F. H.; Stevenson, D.; Sundaram, H. Alpha-amino acid phenolic ester derivatives: novel water-soluble general anesthetic agents which allosterically modulate GABA(A) receptors. J. Med. Chem., 2001, 44, 3582-3591.
28. Rossi, M.; Erlebacher, J.; Zacharias, D. E.; Carrell, H. L.; Iannucci, B. The crystal and molecular structure of ellagic acid dihydrate: a dietary anti-cancer agent. Carcinogenesis, 1991, 12, 2227-2232.
29. Lei, F.; Xing, D. M.; Xiang, L.; Zhao, Y. N.; Wang, W.; Zhang, L. J.; Du, L. J. Pharmacokinetic study of ellagic acid in rat after oral administration of pomegranate leaf extract. J. Chromatogr. B Anal. Technol. Biomed. Life Sci., 2003, 796, 189-194.
30. Bala, I.; Bhardwaj, V.; Hariharan, S.; Kumar, M. N. Analytical methods for assay of ellagic acid and its solubility studies. J. Pharm. Biomed. Anal., 2006, 40, 206-210.
31. Murugan, V.; Mukherjee, K.; Maiti, K.; Mukherjee, P. K. Enhanced oral bioavailability and antioxidant profile of ellagic acid by phospholipids. J. Agric. Food Chem., 2009, 57, 4559-4565.
32. Kimura, Y.; Sumiyoshi, M.; Baba, K. Antitumor activities of synthetic and natural stilbenes through antiangiogenic action. Cancer Sci., 2008, 99, 2083-2096.
33. Lopez-Nicolas, J. M.; Garcia-Carmona, F. Aggregation state and pKa values of (E)-resveratrol as determined by fluorescence spectroscopy and UV-visible absorption. J. Agric. Food Chem., 2008, 56, 7600-7605.
34. Pettit, G. R.; Anderson, C. R.; Gapud, E. J.; Jung, M. K.; Knight, J. C.; Hamel, E.; Pettit, R. K. Antineoplastic agents. 515. Synthesis of human cancer cell growth inhibitors derived from 3,4-methylenedioxy-5,4'-dimethoxy-3'-amino-Z-stilbene. J. Nat. Prod., 2005, 68, 1191-1197.
35. Lamblin, F.; Hano, C.; Fliniaux, O.; Mesnard, F.; Fliniaux, M. A.; Laine, E. Interest of lignans in prevention and treatment of cancers. Med. Sci., 2008, 24, 511-519.
36. Dai, J.; Gupte, A.; Gates, L.; Mumper, R. J. A Comprehensive Study of Anthocyanin-Containing Extracts from Selected Blackberry Cultivars: Extraction Methods, Stability, Anticancer Properties and Mechanisms. Food Chem. Toxicol., 2009, 47, 837-847.
37. Woodward, G.; Kroon, P.; Cassidy, A.; Kay, C. Anthocyanin stability and recovery: implications for the analysis of clinical and experimental samples. J. Agric. Food Chem., 2009, 57, 5271-5278.
38. Spencer, J. P.; Chaudry, F.; Pannala, A. S.; Srai, S. K.; Debnam, E.; Rice-Evans, C. Decomposition of cocoa procyanidins in the gastric milieu. Biochem. Biophys. Res. Commun., 2000, 272, 236-241.
39. Chen, C.; Zhang, Y. Z.; Zheng, H.; Xu, B. B.; Gao, W. Suppression of the obliteration process by ventilation in a mouse orthotopic tracheal transplantation model. Transplantation, 2009, 87, 1762-1768.
40. Wang, R.; Zhou, W.; Jiang, X. Reaction kinetics of degradation and epimerization of epigallocatechin gallate (EGCG) in aqueous system over a wide temperature range. J. Agric. Food Chem., 2008, 56, 2694-2701.
41. Boulton, D. W.; Walle, U. K.; Walle, T. Fate of the flavonoid quercetin in human cell lines: chemical instability and metabolism. J. Pharm. Pharmacol., 1999, 51, 353-359.
42. Kerns, E. H.; Di, L. In: Drug-like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization. Elsevier Inc: Oxford, 2008, pp. 169-177.
43. Weyant, M. J.; Carothers, A. M.; Bertagnolli, M. E.; Bertagnolli, M. M. Colon cancer chemopreventive drugs modulate integrinmediated signaling pathways. Clin. Cancer Res., 2000, 6, 949-956.
44. Scheidweiler, K. B.; Shojaie, J.; Plessinger, M. A.; Wood, R. W.; Kwong, T. C. Stability of methylecgonidine and ecgonidine in sheep plasma in vitro. Clin. Chem., 2000, 46, 1787-1795.
45. Gonthier, M. P.; Cheynier, V.; Donovan, J. L.; Manach, C.; Morand, C.; Mila, I.; Lapierre, C.; Remesy, C.; Scalbert, A. Microbial aromatic acid metabolites formed in the gut account for a major fraction of the polyphenols excreted in urine of rats fed red wine polyphenols. J.Nutr., 2003, 133, 461-467.
46. Del Rio, D.; Costa, L. G.; Lean, M. E.; Crozier, A. Polyphenols and health: What compounds are involved? Nutr. Metab. Cardiovasc. Dis., 2009, 20, 1-6.
47. Evaldson, G.; Heimdahl, A.; Kager, L.; Nord, C. E. The normal human anaerobic microflora. Scand. J. Infect. Dis. Suppl., 1982, 35, 9-15.
48. Blaut, M.; Clavel, T. Metabolic diversity of the intestinal microbiota: implications for health and disease. J. Nutr., 2007, 137, 751-755.
49. Van Nuenen, M. H.; Venema, K.; van der Woude, J. C.; Kuipers, E. J. The metabolic activity of fecal microbiota from healthy individuals and patients with inflammatory bowel disease. Dig. Dis. Sci., 2004, 49, 485-491.
50. Booth, A. N.; Deeds, F.; Jones, F. T.; Murray, C. W. The metabolic fate of rutin and quercetin in the animal body. J. Biol. Chem., 1956, 223, 251-257.
51. Braune, A.; Gutschow, M.; Engst, W.; Blaut, M.Degradation of quercetin and luteolin by Eubacterium ramulus. Appl. Environ. Microbiol., 2001, 67, 5558-5567.
52. Krishnamurty, H. G.; Cheng, K. J.; Jones, G. A.; Simpson, F. J.; Watkin, J. E. Identification of products produced by the anaerobic degradation of rutin and related flavonoids by Butyrivibrio sp. C3. Can. J. Microbiol., 1970, 16, 759-767.
53. Winter, J.; Moore, L. H.; Dowell, V. R., Jr.; Bokkenheuser, V. D.C-ring cleavage of flavonoids by human intestinal bacteria. Appl. Environ. Microbiol., 1989, 55, 1203-1208.
54. Aura, A. M.; Martin-Lopez, P.; O'Leary, K. A.; Williamson, G.; Oksman-Caldentey, K. M.; Poutanen, K.; Santos-Buelga, C. In vitro metabolism of anthocyanins by human gut microflora. Eur. J. Nutr., 2005, 44, 133-142.
55. Keppler, K.; Humpf, H. U. Metabolism of anthocyanins and their phenolic degradation products by the intestinal microflora. Bioorg. Med. Chem., 2005, 13, 5195-5205.
56. Yuan, J. P.; Wang, J. H.; Liu, X. Metabolism of dietary soy isoflavones to equol by human intestinal microflora--implications for health. Mol. Nutr. Food Res., 2007, 51, 765-781.
57. Gonthier, M. P.; Verny, M. A.; Besson, C.; Remesy, C.; Scalbert, A. Chlorogenic acid bioavailability largely depends on its metabolism by the gut microflora in rats. J. Nutr., 2003, 133, 1853-1859.
58. Kim, D. H.; Jung, E. A.; Sohng, I. S.; Han, J. A.; Kim, T. H.; Han, M. J. Intestinal bacterial metabolism of flavonoids and its relation to some biological activities. Arch. Pharm. Res., 1998, 21, 17-23.
59. Konishi, Y.; Kobayashi, S. Transepithelial transport of rosmarinic acid in intestinal Caco-2 cell monolayers. Biosci. Biotechnol. Biochem., 2005, 69, 583-591.
60. Deprez, S.; Brezillon, C.; Rabot, S.; Philippe, C.; Mila, I.; Lapierre, C.; Scalbert, A. Polymeric proanthocyanidins are catabolized by human colonic microflora into low-molecular-weight phenolic acids. J. Nutr., 2000, 130, 2733-2738.
61. Morteau, O. In: Oral tolerance: the response of the intestinal mucosa to dietary antigens Kluwer academic/plenum: Georgetown, 2004, pp. 1-12.
62. Yan, Z.; Caldwel, G.W. In: Optimization in Drug Discovery in vitro methods, Jannicelli, J; Kopf, W., Ed; Humana Press: Totowa, 2004, pp. 19-35.
63. Serra, H.; Mendes, T.; Bronze, M. R.; Simplicio, A. L. Prediction of intestinal absorption and metabolism of pharmacologically active flavones and flavanones. Bioorg. Med.Chem., 2008, 16, 4009-4018.
64. Tian, X.; Yang, X.; Wang, K. The efflux of flavonoids morin, isorhamnetin-3-O-rutinoside and diosmetin-7-O-beta-D-xylopyranosyl-(1-6) -beta-D-glucopyranoside in the human intestinal cell line caco-2. Pharm. Res., 2006, 23, 1721-1728.
65. Hur, H. G.; Lay, J. O., Jr.; Beger, R. D.; Freeman, J. P.; Rafii, F. Isolation of human intestinal bacteria metabolizing the natural isoflavone glycosides daidzin and genistin. Arch. Microbiol., 2000, 174, 422-428.
66. Brand, W.; van der Wel, P. A.; Rein, M. J.; Barron, D.; Williamson, G.; van Bladeren, P. J.; Rietjens, I. M. Metabolism and transport of the citrus flavonoid hesperetin in Caco-2 cell monolayers. Drug. Metab. Dispos., 2008, 36, 1794-1802.
67. Alvarez, A. I.; Real, R.; Perez, M.; Mendoza, G.; Prieto, J. G.; Merino, G. Modulation of the activity of ABC transporters (Pglycoprotein, MRP2, BCRP) by flavonoids and drug response. J. Pharm. Sci., 2010, 99, 598-617.
68. Dorant, E.; van den Brandt, P. A.; Goldbohm, R. A.; Sturmans, F. Consumption of onions and a reduced risk of stomach carcinoma. Gastroenterology, 1996, 110, 12-20.
69. Walgren, R. A.; Walle, U. K.; Walle, T. Transport of quercetin and its glucosides across human intestinal epithelial Caco-2 cells. Biochem. Pharmacol., 1998, 55, 1721-1727.
70. Walgren, R. A.; Karnaky, K. J., Jr.; Lindenmayer, G. E.; Walle, T. Efflux of dietary flavonoid quercetin 4'-beta-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance-associated protein-2. J. Pharmacol. Exp. Ther., 2000, 294, 830-836.
71. Katiyar, S. K.; Agarwal, R.; Mukhtar, H. Green tea in chemoprevention of cancer. Compr. Ther., 1992, 18, 3-8.
72. Vaidyanathan, J. B.; Walle, T. Glucuronidation and sulfation of the tea flavonoid (-)-epicatechin by the human and rat enzymes. Drug Metab. Dispos., 2002, 30, 897-903.
73. Chen, L.; Lee, M. J.; Li, H.; Yang, C. S. Absorption, distribution, elimination of tea polyphenols in rats. Drug Metab. Dispos., 1997, 25, 1045-1050.
74. Chow, H. H.; Cai, Y.; Alberts, D. S.; Hakim, I.; Dorr, R.; Shahi, F.; Crowell, J. A.; Yang, C. S.; Hara, Y. Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol. Biomarkers Prev., 2001, 10, 53-58.
75. Zhu, M.; Chen, Y.; Li, R. C. Oral absorption and bioavailability of tea catechins. Planta Med., 2000, 66, 444-447.
76. Vaidyanathan, J. B.; Walle, T. Transport and metabolism of the tea flavonoid (-)-epicatechin by the human intestinal cell line Caco-2. Pharm. Res., 2001, 18, 1420-1425.
77. Vaidyanathan, J. B.; Walle, T. Cellular uptake and efflux of the tea flavonoid (-)epicatechin-3-gallate in the human intestinal cell line Caco-2. J. Pharmacol. Exp. Ther., 2003, 307, 745-752.
78. Merillon, J. M.; Fauconneau, B.; Teguo, P. W.; Barrier, L.; Vercauteren, J.; Huguet, F. Antioxidant activity of the stilbene astringin, newly extracted from Vitis vinifera cell cultures. Clin. Chem., 1997, 43,1092-1093.
79. Day, A. J.; DuPont, M. S.; Ridley, S.; Rhodes, M.; Rhodes, M. J.; Morgan, M. R.; Williamson, G. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver betaglucosidase activity. FEBS Lett., 1998, 436, 71-75.
80. Soleas, G. J.; Angelini, M.; Grass, L.; Diamandis, E. P.; Goldberg, D. M. Absorption of trans-resveratrol in rats. Methods Enzymol., 2001, 335, 145-154.
81. Henry, C.; Vitrac, X.; Decendit, A.; Ennamany, R.; Krisa, S.; Merillon, J. M. Cellular uptake and efflux of trans-piceid and its aglycone trans-resveratrol on the apical membrane of human intestinal Caco-2 cells. J. Agric. Food Chem., 2005, 53, 798-803.
82. Madgula, V. L.; Avula, B.; Choi, Y. W.; Pullela, S. V.; Khan, I. A.; Walker, L. A.; Khan, S. I. Transport of Schisandra chinensis extract and its biologically-active constituents across Caco-2 cell monolayers - an in-vitro model of intestinal transport. J. Pharm. Pharmacol., 2008, 60, 363-370.
83. Cao, J.; Chen, X.; Liang, J.; Yu, X. Q.; Xu, A. L.; Chan, E.; Wei, D.; Huang, M.; Wen, J. Y.; Yu, X. Y.; Li, X. T.; Sheu, F. S.; Zhou, S. F. Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra. Drug Metab. Dispos., 2007, 35,539-553.
84. Lv, P.; Huang, X. W.; Lv, Q. J. Advances in studies on absorption, distribution, metabolism of flavonoids. Zhongguo Zhong Yao Za Zhi, 2007, 32, 1961-19744.
85. Manach, C.; Donovan, J. L. Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radic. Res., 2004, 38,771-785.
86. Zhang, L.; Zuo, Z.; Lin, G. Intestinal and hepatic glucuronidation of flavonoids. Mol. Pharm., 2007, 4, 833-845.
87. Kiang, T. K.; Ensom, M. H.; Chang, T. K. UDPglucuronosyltransferases and clinical drug-drug interactions. Pharmacol. Ther., 2005, 106, 97-132.
88. Ohno, S.; Nakajin, S. Determination of mRNA expression of human UDP-glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptasepolymerase chain reaction. Drug Metab. Dispos., 2009, 37, 32-40.
89. Cermak, R.; Landgraf, S.; Wolffram, S. The bioavailability of quercetin in pigs depends on the glycoside moiety and on dietary factors. J. Nutr., 2003, 133, 2802-2807.
90. Van der Woude, H.; Boersma, M. G.; Vervoort, J.; Rietjens, I. M. Identification of 14 quercetin phase II mono- and mixed conjugates and their formation by rat and human phase II in vitro model systems. Chem. Res. Toxicol., 2004, 17, 1520-1530.
91. Chen, J.; Lin, H.; Hu, M. Absorption and metabolism of genistein and its five isoflavone analogs in the human intestinal Caco-2 model. Cancer Chemother. Pharmacol., 2005, 55, 159-169.
92. Sabolovic, N.; Humbert, A. C.; Radominska-Pandya, A.; Magdalou, J. Resveratrol is efficiently glucuronidated by UDPglucuronosyltransferases in the human gastrointestinal tract and in Caco-2 cells. Biopharm. Drug Dispos., 2006, 27, 181-189.
93. Ruefer, C. E.; Gerhauser, C.; Frank, N.; Becker, H.; Kulling, S. E. In vitro phase II metabolism of xanthohumol by human UDPglucuronosyltransferases and sulfotransferases. Mol. Nutr. Food Res., 2005, 49, 851-856.
94. Tang, L.; Singh, R.; Liu, Z.; Hu, M. Structure and concentration changes affect characterization of UGT isoform-specific metabolism of isoflavones. Mol. Pharm., 2009, 6, 1466-1482.
95. Spencer, J. P. Metabolism of tea flavonoids in the gastrointestinal tract. J. Nutr., 2003, 133, 3255-3261.
96. Zhang, L.; Lin, G.; Zuo, Z. Involvement of UDPglucuronosyltransferases in the extensive liver and intestinal firstpass metabolism of flavonoid baicalein. Pharm. Res., 2007, 24, 81-89.
97. Collins, Q. F.; Liu, H. Y.; Pi, J.; Liu, Z.; Quon, M. J.; Cao, W. Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5'-AMP-activated protein kinase. J. Biol. Chem., 2007, 282, 30143-30149.
98. Hulten, K.; Winkvist, A.; Lenner, P.; Johansson, R.; Adlercreutz, H.; Hallmans, G. An incident case-referent study on plasma enterolactone and breast cancer risk. Eur. J. Nutr., 2002, 41, 168-176.
99. Maier-Salamon, A.; Hagenauer, B.; Reznicek, G.; Szekeres, T.; Thalhammer, T.; Jager, W. Metabolism and disposition of resveratrol in the isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides. J. Pharm. Sci., 2008, 97, 1615-1628.
100. Jan, K. C.; Hwang, L. S.; Ho, C. T. Tissue distribution and elimination of sesaminol triglucoside and its metabolites in rat. Mol. Nutr. Food Res., 2009, 53, 815-825.
101. Bolling, B. W.; Court, M. H.; Blumberg, J. B.; Chen, C. Y. The kinetic basis for age-associated changes in quercetin and genistein glucuronidation by rat liver microsomes. J. Nutr. Biochem., 2009 (ahead of print),
102. Zhou, S.; Kestell, P.; Tingle, M. D.; Paxton, J. W. Gender differences in the metabolism and pharmacokinetics of the experimental anticancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Cancer Chemother. Pharmacol., 2002, 49, 126-132.
103. Murota, K.; Terao, J. Quercetin appears in the lymph of unanesthetized rats as its phase II metabolites after administered into the stomach. FEBS Lett., 2005, 579, 5343-5346.
104. Boersma, M. G.; van der Woude, H.; Bogaards, J.; Boeren, S.; Vervoort, J.; Cnubben, N. H.; van Iersel, M. L.; van Bladeren, P. J.; Rietjens, I. M. Regioselectivity of phase II metabolism of luteolin and quercetin by UDP-glucuronosyl transferases. Chem. Res. Toxicol., 2002, 15, 662-670.
105. Gradolatto, A.; Canivenc-Lavier, M. C.; Basly, J. P.; Siess, M. H.; Teyssier, C. Metabolism of apigenin by rat liver phase I and phase ii enzymes and by isolated perfused rat liver. Drug Metab. Dispos., 2004, 32, 58-65.
106. Abe, K.; Inoue, O.; Yumioka, E. Biliary excretion of metabolites of baicalin and baicalein in rats. Chem. Pharm. Bull., 1990, 38, 209-211.
107. Androutsopoulos, V. P.; Mahale, S.; Arroo, R. R.; Potter, G. Anticancer effects of the flavonoid diosmetin on cell cycle progression and proliferation of MDA-MB 468 breast cancer cells due to CYP1 activation. Oncol. Rep., 2009, 21, 1525-1528.
108. Graf, B. A.; Ameho, C.; Dolnikowski, G. G.; Milbury, P. E.; Chen, C. Y.; Blumberg, J. B. Rat gastrointestinal tissues metabolize quercetin. J. Nutr., 2006, 136, 39-44.
109. Mullen, W.; Rouanet, J. M.; Auger, C.; Teissedre, P. L.; Caldwell, S. T.; Hartley, R. C.; Lean, M. E.; Edwards, C. A.; Crozier, A. Bioavailability of [2-(14)C]quercetin-4'-glucoside in rats. J. Agric. Food Chem., 2008, 56, 12127-12137.
110. Xu, H.; Kulkarni, K. H.; Singh, R.; Yang, Z.; Wang, S. W.; Tam, V. H.; Hu, M. Disposition of naringenin via glucuronidation path way is affected by compensating efflux transporters of hydrophilic glucuronides. Mol. Pharm., 2009, 6, 1703-1715.
111. Gamage, N.; Barnett, A.; Hempel, N.; Duggleby, R. G.; Windmill, K. F.; Martin, J. L.; McManus, M. E. Human sulfotransferases and their role in chemical metabolism. Toxicol. Sci., 2006, 90, 5-22.
112. Ganguly, T. C.; Krasnykh, V.; Falany, C. N. Bacterial expression and kinetic characterization of the human monoamine-sulfating form of phenol sulfotransferase. Drug Metab. Dispos., 1995, 23, 945-950.
113. Jeong, E. J.; Jia, X.; Hu, M. Disposition of formononetin via enteric recycling: metabolism and excretion in mouse intestinal perfusion and Caco-2 cell models. Mol. Pharm., 2005, 2, 319-328.
114. Hu, M.; Chen, J.; Lin, H. Metabolism of flavonoids via enteric recycling: mechanistic studies of disposition of apigenin in the Caco-2 cell culture model. J. Pharmacol. Exp. Ther., 2003, 307, 314-321.
115. Walle, T.; Hsieh, F.; De Legge, M. H.; Oatis, J. E., Jr.; Walle, U. K. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos., 2004, 32, 1377-1382.
116. Ford, R. A.; Hawkins, D. R.; Mayo, B. C.; Api, A. M. The in vivo dermal absorption and metabolism of [4-14C] coumarin by rats and by human volunteers under simulated conditions of use in fragrances. Food Chem. Toxicol., 2001, 39, 153-162.
117. Liao, C. D.; Hung, W. L.; Lu, W. C.; Jan, K. C.; Shih, D. Y.; Yeh, A. I.; Ho, C. T.; Hwang, L. S. Differential tissue distribution of sesaminol triglucoside and its metabolites in rats fed with lignan glycosides from sesame meal with or without nano/submicrosizing. J. Agric. Food Chem., 2009, 58, 563-569.
118. O'Leary, K. A.; Day, A. J.; Needs, P. W.; Mellon, F. A.; O'Brien, N. M.; Williamson, G. Metabolism of quercetin-7- and quercetin-3-glucuronides by an in vitro hepatic model: the role of human betaglucuronidase, sulfotransferase, catechol-O-methyltransferase and multi-resistant protein 2 (MRP2) in flavonoid metabolism. Biochem. Pharmacol., 2003, 65, 479-491.
119. Kaldas, M. I.; Walle, U. K.; Walle, T. Resveratrol transport and metabolism by human intestinal Caco-2 cells. J. Pharm. Pharmacol., 2003, 55, 307-312.
120. Gradolatto, A.; Basly, J. P.; Berges, R.; Teyssier, C.; Chagnon, M. C.; Siess, M. H.; Canivenc-Lavier, M. C. Pharmacokinetics and metabolism of apigenin in female and male rats after a single oral administration. Drug. Metab. Dispos., 2005, 33, 49-54.
121. Gibson, G. G.; Skett, P. In: Introduction to Drug Metabolism. Nelson Thornes, Cheltenham, 2003, pp. 2-14.
122. Rendic, S.; Di Carlo, F. J. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab. Rev., 1997, 29, 413-580.
123. Lewis, D. F. Human cytochromes P450 associated with the phase 1 metabolism of drugs and other xenobiotics: a compilation of substrates and inhibitors of the CYP1, CYP2 and CYP3 families. Curr. Med. Chem., 2003, 10, 1955-1972.
124. Rendic, S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab. Rev., 2002, 34, 83-448.
125. Breinholt, V.; Hossaini, A.; Svendsen, G. W.; Brouwer, C.; Nielsen, E. Estrogenic activity of flavonoids in mice. The importance of estrogen receptor distribution, metabolism and bioavailability. Food Chem. Toxicol., 2000, 38, 555-564.
126. Lewis, D. F.; Ito, Y.; Lake, B. G. Metabolism of coumarin by human P450s: a molecular modelling study. Toxicol. In Vitro, 2006, 20, 256-264.
127. Galijatovic, A.; Otake, Y.; Walle, U. K.; Walle, T. Extensive metabolism of the flavonoid chrysin by human Caco-2 and Hep G2 cells. Xenobiotica, 1999, 29, 1241-1256.
128. Otake, Y.; Hsieh, F.; Walle, T. Glucuronidation versus oxidation of the flavonoid galangin by human liver microsomes and hepatocytes. Drug Metab. Dispos., 2002, 30, 576-581.
129. Lambert, J. D.; Hong, J.; Kim, D. H.; Mishin, V. M.; Yang, C. S. Piperine enhances the bioavailability of the tea polyphenol (-)-epigallocatechin-3-gallate in mice. J. Nutr., 2004, 134, 1948-1952.
130. Shoba, G.; Joy, D.; Joseph, T.; Majeed, M.; Rajendran, R.; Srinivas, P. S. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998, 64, 353-356.
131. Cermak, R.Effect of dietary flavonoids on pathways involved in drug metabolism. Expert. Opin. Drug Metab. Toxicol., 2008, 4, 17-35.
132. Selma, M. V.; Espin, J. C.; Tomas-Barberan, F. A. Interaction between phenolics and gut microbiota: role in human health. J. Agric. Food Chem., 2009, 57, 6485-6501.