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Title: Flavonoid metabolism and bioactivities in a prostate cancer cell model
Author: Xu, Juan
ISNI:       0000 0001 2411 0413
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Flavonoids are promising candidate agents for chemoprevention in prostate cancer. However, only a few flavonoids have been investigated and studies on effects of flavonoid metabolites are rarely reported. Glucuronides of eight flavonoids were enzymatically-synthesised and impact on prostate cancer LNCaP cells in comparison with their parent flavonoid was assessed. The molecular mechanism was explored by studying expression of uridine 5'-di phospho-gl ucuronosy I transferase (UOT), catechol-O-methyltransferase (COMT) and estrogen receptor (ER)-β in LNCaP cells. All flavonoids were glucuronidated by LNCaP cells, but to different extents. Catechol flavonoids were methylated prior to glucuronidation, the methyl form predominating. Methylation was inhibited by 3, 5-dinitrocatecol (DNC; a COMT inhibitor), conversely hesperetin, genistein and naringenin glucuronidation was increased by co-incubation of DNC. Apigenin, luteolin, quercetin and isorhamnetin showed cytotoxic effects on LNCaP cells. All metabolites demonstrated reduced cytotoxicity compared to parent compounds, except genistein glucuronide. Co-incubation of catechol-flavonoids with DNC reduced cytotoxicity, and DNC alone dose-dependently stimulated cell proliferation. Ascorbic acid with luteolin or quercetin showed synergistic effects on cytotoxicity at physiologically achievable concentrations. Glucuronidation of testosterone in LNCaP cells was enhanced by flavonoids in a dose-dependent manner. Flavonoid metabolite mixtures had reduced activity however, the purified glucuronides displayed higher activity, showing position of glucuronide conjugation is significant. DNC co-treatment with flavonoids reduced their potential to enhance UGT activity. Luteolin, quercetin, apigenin and genistein significantly increased UGT2B17 expression. UGT2B15 expression was enhanced by eriodictyol, genistein, hesperetin, kaempferol and nanngemn. DNC dose-dependently down-regulated expression of UGT2B 17, while up-regulating UGT2BI5. All flavonoids, except homoeriodictyol, enhanced COMT activity toward luteolin; genistein demonstrated the highest activity. Genistein and hesperetin-treated cells significantly increased COMT expression. COMT was down-regulated by increasing concentration of DNC. Flavonoids up-regulated the expression of ER~ 1 but showed varying effects on ER~2 and ER~5 isoforms. Overall, the data demonstrates an interaction of flavonoids and flavonoid glucuronides with LNCaP cells. Flavonoids differentially regulate the expression of UGT, COMT, and ER~ isoforms; upregulation of UGT2B 17 appears to be correlated to the cytotoxic effects observed. Future studies should continue to determine the bioactive potential for flavonoids and metabolites in chemoprevention of prostate cancer
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available