Green tea (Camellia sinensis)
Inhibitory effects of commonly used herbal extracts on UDP-glucuronosyltransferase 1A4, 1A6, and 1A9 enzyme activities
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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 (IC(50)) and the volume in which the dose could be diluted to generate an IC(50)-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 IC(50) value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC(50) 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 IC(50) values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC(50)-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.
1 . Inhibition of UGT1A9 by Epigallocatechin Gallate (id=NPDI-mzhpNw)
In Vitro Enzyme Inhibition Experiment
Inhibition was detected. Cutoff used — >20% inhibiton vs. control
- UGT1A9
Cell fraction Pooled human liver microsomes -7999662
Results
Percent inhibition was estimated from Fig. 1. Epigallocaetchin gallate at 250 mg in 53 and 5.3 L did not inhibit UGT1A9-mediated mycophenolic acid 7-O-glucuronide formation.
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
0.16 mg/mL
Commercially available
100 µL
30 min
UDPGA
Not available
Not available
240 µM
250 mg in 0.53 L
2 . Inhibition of UGT1A6 by Epigallocatechin Gallate (id=NPDI-Dg01cQ)
In Vitro Enzyme Inhibition Experiment
Inhibition was detected. Cutoff used — >20% inhibiton vs. control
- UGT1A6
Cell fraction Pooled human liver microsomes -7999662
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
0.5 mg/mL
Commercially available
100 µL
60 min
UDPGA
8 mM
250 mg in 53, 5.3, and 0.53 L
3 . Inhibition of UGT1A4 by Epigallocatechin Gallate (id=NPDI-URZBxQ)
In Vitro Enzyme Inhibition Experiment
Inhibition was detected. Cutoff used — >20% inhibiton vs. control
- UGT1A4
Cell fraction Pooled human liver microsomes -7999662
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
0.1 mg/mL
Commercially available
20 min
UDPGA
Not available
Not available
60 µM
0.05-1000 µg/mL (estimated from Fig. 2)