Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine Is a Relatively Selective CYP3A4 Inhibitor

Laurie P. Volak; Senait Ghirmai; John R. Cashman; Michael H. Court

doi:10.1124/dmd.108.020552

Abstract

Curcuminoid extract and piperine are being evaluated for beneficial effects in Alzheimer's disease, among other intractable disorders. Consequently, we studied the potential for herb-drug interactions involving cytochrome P450 (P450), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes. The curcuminoid extract inhibited SULT > CYP2C19 > CYP2B6 > UGT > CYP2C9 > CYP3A activities with IC₅₀ values ranging from 0.99 ± 0.04 to 25.3 ± 1.3 μM, whereas CYP2D6, CYP1A2, and CYP2E1 activities were less affected (IC₅₀ values >60 μM). Inhibition of CYP3A activity by curcuminoid extract was consistent with competitive inhibition (K_i = 11.0 ± 1.3 μM), whereas inhibition of both CYP2C9 and CYP2C19 activities were consistent with mixed competitive-noncompetitive inhibition (10.6 ± 1.1 and 7.8 ± 0.9 μM, respectively). Piperine was a relatively selective noncompetitive inhibitor of CYP3A (IC₅₀ 5.5 ± 0.7 μM, K_i = 5.4 ± 0.3 μM) with less effect on other enzymes evaluated (IC₅₀ > 29 μM). Curcuminoid extract and piperine inhibited recombinant CYP3A4 much more potently (by >5-fold) than CYP3A5. Pure synthetic curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) were also evaluated for their effects on CYP3A, CYP2C9, UGT, and SULT activities. All three curcuminoids had similar effects on CYP3A, UGT, and SULT activity, but demethoxycurcumin (IC₅₀ = 8.8 ± 1.2 μM) was more active against CYP2C9 than either curcumin or bisdemethoxycurcumin (IC₅₀ > 50 μM). Based on these data and expected tissue concentrations of inhibitors, we predict that a p.o. administered curcuminoid/piperine combination is most likely to inhibit CYP3A, CYP2C9, UGT, and SULT metabolism within the intestinal mucosa.

Footnotes

↵1 Information about curcuminoid clinical trials was also obtained on July 3, 2007, from http://www.clinicaltrials.gov by searching for the keyword “curcumin.” Specific ClinicalTrials.gov identifiers for trials mentioned in text are NCT00094445, NCT00113841, and NCT00099710.
This publication was made possible by Grant F31AT003973 from the National Center for Complementary and Alternative Medicine (NCCAM), National Institutes of Health (Bethesda, MD) to L.P.V. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM or the National Institutes of Health. Other support was also provided by Grants R01GM061834 and R21GM074369 from the National Institute of General Medical Sciences (NIGMS), National Institutes of Health (Bethesda, MD), to M.H.C. and a grant from the Alzheimer's Drug Discovery Foundation (ADDF) (http://www.alzdiscovery.org.) to J.R.C. The ADDF catalyzes and funds drug discovery and drug development for Alzheimer's disease and cognitive aging.
Parts of this work were originally presented at the 14th North American ISSX Meeting, Rio Grande, Puerto Rico (2006), and the 36th American College of Clinical Pharmacology Annual Meeting, San Francisco, CA (2007).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.108.020552.
ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; SULT, sulfotransferase; P450, cytochrome P450; HLC, human liver cytosol; HLM, human liver microsome; EGCG, (-)-epigallocatechin-3-gallate; ESI-MS, electrospray ionization-mass spectrometry; EtOAc, ethyl acetate; HPLC, high-performance liquid chromatography; DMSO, dimethyl sulfoxide; LC/MS, liquid chromatography/mass spectrometry; PKC, protein kinase C.
- Received January 22, 2008.
- Accepted May 12, 2008.