Premium
PI‐49
Author(s) -
Iyer L. V.,
Furimsky A. M.,
Li Y.,
Green C. E.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.070
Subject(s) - glucuronidation , genistein , daidzein , chemistry , sn 38 , chrysin , pharmacology , microsome , quercetin , flavonoid , biochanin a , metabolite , isoflavones , bioavailability , irinotecan , glucuronide , s9 fraction , ic50 , biochemistry , enzyme , medicine , in vitro , colorectal cancer , cancer , antioxidant
BACKGROUND This study was performed to investigate the influence of dietary flavonoids on the glucuronidation of SN‐38, the active metabolite of the anticancer agent, irinotecan. SN‐38 is glucurono‐conjugated by UGT1A1 (Iyer et al , JClin Invest, 1998). Dietary flavonoids such as chrysin and quercetin (from fruits) and daidzein and genistein (from soy) are known to be substrates or inducers of glucuronidation and hence have the potential to modify SN‐38 glucuronidation. METHODS SN‐38 glucuronidation was studied using pooled human liver microsomes (HLM), rat liver microsomes (RLM) and cDNA expressed human UGT1A1 in presence of each flavonoid. SN‐38 glucuronide formation was measured using an HPLC method. RESULTS Genistein exhibited potent inhibition of SN‐38 glucuronidation, especially after incubations with HLM and human UGT1A1 with low IC 50 values of 4 and 3 μM. Daidzein and quercetin moderately inhibited SN‐38 glucuronidation (IC 50 of 7 to 20 μM), while chrysin did not have a major influence on SN‐38 glucuronidation except at concentrations > 30 μM. (See Table)IC 50 (μM) Flavonoid RLM HLM UGT1A1Chrysin 60 50 30 Quercetin 7 20 15 Daidzein 10 15 17 Genistein 7 4 3CONCLUSIONS Genistein, a significant component of dietary soy products, inhibited SN‐38 glucuronidation at pharmacologically relevant concentrations. Hence, concomitant administration of soy products with irinotecan may influence the disposition and toxicity of irinotecan by inhibiting the glucuronidation of SN‐38. Clinical Pharmacology & Therapeutics (2005) 79 , P20–P20; doi: 10.1016/j.clpt.2005.12.070