Effects Of Curcuma Xanthorrhiza Roxb. On Phase Ii Drug Metabolizing Enzymes

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Date
2015-05
Authors
MOHD SALLEH, NURUL AFIFAH
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Abstract
Curcuma xanthorrhiza is traditionally utilized for a range of illness including liver damage, hypertension and cancer. Since the consumption of herbal health supplements together with modern medications had increased, the risk of herb-drug interaction may also increase. UDP-glucuronosyltransferase (UGT) and glutathione transferase (GST) are phase II enzymes which are involved in metabolism of numerous xenobiotic and endogenous substances. Induction or inhibition of UGT and GST enzyme by Curcuma xanthorrhiza may affect the metabolism of drugs that are highly metabolized by these enzymes. In this study, the effects of aqueous and ethanol extracts of Curcuma xanthorrhiza and their three main constituents, namely curcumene, curcumin and xanthorrhizol on UGT and GST activity in vitro were investigated. Two in vitro models, rat liver and recombinant expressed enzyme were employed as the enzyme sources to access the inhibition studies. In rat liver microsome, UGT activity was inhibited by the ethanol extract with IC50 values of 279.74 ± 16.33 μg/mL. Assessment towards UGT1A1 and UGT2B7 isoforms has shown higher inhibition by Curcuma xanthorrhiza extracts based on the IC50 values obtained. Highest inhibitions towards both isoforms were demonstrated by ethanol extract (IC50 for UGT1A1 = 22.76 ± 7.20 ug/mL, UGT2B7 = 9.59 ± 1.37 ug/mL) as compared to the aqueous extract (IC50 for UGT1A1 = 110.71 ± 26.49 ug/mL, UGT2B7 = 526.65 ± 31.65 ug/mL). Similar studies conducted using rat liver microsome have shown no inhibition of UGT activity by Curcuma xanthorrhiza constituents. However, curcumin and xanthorrhizol were the better inhibitors of UGT1A1 (IC50 = 6.76 ± 2.92 μM for curcumin and 11.30 ± 0.27 μM for xanthorrhizol) as compared to UGT2B7 (IC50 = 32.50 ± 0.26 μM for curcumin and 42.11 ± 19.84 μM for xanthorrhizol). Curcuma xanthorrhiza extracts and constituents were screened for the inhibition of cytosolic rat liver GST, recombinant mouse GST Mu-1 (mGSTM1) and recombinant human GST Pi-1 (hGSTP1). The results obtained demonstrated that cytosolic rat liver GST was inhibited by ethanol extract with IC50 value of 292.38 ± 20.16 ug/mL while mGSTM1 was strongly inhibited by ethanol extract (IC50= 20.11 ± 2.38 ug/mL), followed by weak inhibition by aqueous extract (IC50= 648.72 ± 51.30 ug/mL). As for hGSTP1, the ethanol extract demonstrated the highest inhibition (IC50 = 128.88 ± 8.61 μg/mL) while the aqueous extract demonstrated weak inhibition with an IC50 value of 726.04 ± 57.35 μg/mL. Curcumin demonstrated strongest inhibition on mGSTM1 (IC50= 5.23 ± 0.29 uM) followed by hGSTP1 (IC50= 39.13 ± 6.43 μM). These findings suggest that Curcuma xanthorrhiza has the potential to cause herb-drug interaction with drugs or substrates that are primarily metabolized by UGT and GST enzymes. Future studies are needed to evaluate the clinical significance of this interaction.
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Effects Of Curcuma Xanthorrhiza Roxb , On Phase Ii Drug Metabolizing Enzymes
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