Abstract
The aim of this study was to investigate the effect of commonly used botanicals on UDP-glucuronosyltransferase (UGT) 1A4, UGT1A6, and UGT1A9 activities in human liver microsomes. The extracts screened were black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, and valerian in addition to the green tea catechin epigallocatechin gallate (EGCG). Formation of trifluoperazine glucuronide, serotonin glucuronide, and mycophenolic acid phenolic glucuronide was used as an index reaction for UGT1A4, UGT1A6, and UGT1A9 activities, respectively, in human liver microsomes. Inhibition potency was expressed as the concentration of the inhibitor at 50% activity (IC50) and the volume in which the dose could be diluted to generate an IC50-equivalent concentration [volume/dose index (VDI)]. Potential inhibitors were EGCG for UGT1A4, milk thistle for both UGT1A6 and UGT1A9, saw palmetto for UGT1A6, and cranberry for UGT1A9. EGCG inhibited UGT1A4 with an IC50 value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC50 values of 59.5 ± 3.6 and 33.6 ± 3.1 μg/ml, respectively. Saw palmetto and cranberry weakly inhibited UGT1A6 and UGT1A9, respectively, with IC50 values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC50-equivalent concentrations in vivo. VDI values for inhibitors indicate a potential for inhibition of first-pass glucuronidation of UGT1A4, UGT1A6, and UGT1A9 substrates. These results highlight the possibility of herb-drug interactions through modulation of UGT enzyme activities. Further clinical studies are warranted to investigate the in vivo extent of the observed interactions.
Footnotes
This work was supported in part by the National Institutes of Health National Center for Complementary and Alternative Medicine [Grant R21-AT005083].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039602.
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ABBREVIATIONS:
- UGT
- UDP-glucuronosyltransferase
- TFP
- trifluoperazine
- UDPGA
- UDP-glucuronic acid
- BSA
- bovine serum albumin
- EGCG
- epigallocatechin gallate
- MPA
- mycophenolic acid
- MPAG
- mycophenolic acid-7-O-glucuronide
- MPA-d3-G
- mycophenolic acid-d3-β-d-glucuronide
- HLM
- human liver microsome(s)
- HPLC
- high-performance liquid chromatography
- TFPG
- TFP glucuronide
- VDI
- volume per dose index
- HIM
- human intestinal microsomes.
- Received March 16, 2011.
- Accepted June 1, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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