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Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine Is a Relatively Selective CYP3A4 Inhibitor
Open accessAbstract
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 IC(50) values ranging from 0.99 +/- 0.04 to 25.3 +/- 1.3 microM, whereas CYP2D6, CYP1A2, and CYP2E1 activities were less affected (IC(50) values > 60 microM). Inhibition of CYP3A activity by curcuminoid extract was consistent with competitive inhibition (K(i) = 11.0 +/- 1.3 microM), whereas inhibition of both CYP2C9 and CYP2C19 activities were consistent with mixed competitive-noncompetitive inhibition (10.6 +/- 1.1 and 7.8 +/- 0.9 microM, respectively). Piperine was a relatively selective noncompetitive inhibitor of CYP3A (IC(50) 5.5 +/- 0.7 microM, K(i) = 5.4 +/- 0.3 microM) with less effect on other enzymes evaluated (IC(50) > 29 microM). 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 (IC(50) = 8.8 +/- 1.2 microM) was more active against CYP2C9 than either curcumin or bisdemethoxycurcumin (IC(50) > 50 microM). 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.
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TL;DR
Curcuminoid extract inhibited multiple human CYP, UGT, and SULT enzymes in vitro, with SULT and CYP2C19 among the most sensitive, while piperine was a relatively selective CYP3A inhibitor. The authors predict that orally administered curcuminoid/piperine combinations are most likely to inhibit CYP3A, CYP2C9, UGT, and SULT metabolism in the intestinal mucosa.
Key findings
- Curcuminoid extract inhibited SULT > CYP2C19 > CYP2B6 > UGT > CYP2C9 > CYP3A activities, with IC50 values from 0.99 ± 0.04 to 25.3 ± 1.3 μM; CYP2D6, CYP1A2, and CYP2E1 were less affected (IC50 >60 μM). Specific values included SULT in human liver cytosol 0.99 ± 0.04 μM, CYP2C19 7.4 ± 1.2 μM, CYP2B6 9.4 ± 1.9 μM, CYP2C9 13.5 ± 1.4 μM, and CYP3A 25.3 ± 1.3 μM.
- Piperine was a relatively selective noncompetitive CYP3A inhibitor (IC50 5.5 ± 0.7 μM; Ki = 5.4 ± 0.3 μM), with less effect on other enzymes evaluated (IC50 >29 μM; CYP2C9 40.7 ± 4.1 μM, CYP1A2 29.8 ± 3.6 μM, others >50 μM).
- Curcuminoid extract and piperine inhibited recombinant CYP3A4 much more potently than CYP3A5: curcuminoid extract IC50 20.3 ± 0.7 μM vs >200 μM; piperine IC50 8.0 ± 1.8 μM vs >50 μM.
- Among pure synthetic curcuminoids, demethoxycurcumin was more active against CYP2C9 (IC50 8.8 ± 1.2 μM) than curcumin or bisdemethoxycurcumin (IC50 >50 μM); all three had similar effects on CYP3A, UGT, and SULT activity. Curcumin had a lower IC50 for acetaminophen glucuronidation in intact LS180 cells (2.2 ± 0.1 μM).
Methods
- In vitro study using human liver microsomes, human liver cytosol, recombinant CYP3A4 and CYP3A5, and LS180 colon cells. CYP probe activities included triazolam 1′-hydroxylation (CYP3A), flurbiprofen hydroxylation (CYP2C9), S-mephenytoin hydroxylation (CYP2C19), phenacetin de-ethylation (CYP1A2), dextromethorphan demethylation (CYP2D6), chlorzoxazone hydroxylation (CYP2E1), and bupropion hydroxylation (CYP2B6); UGT and SULT activities used acetaminophen glucuronidation and sulfation.
- IC50 and Ki values were determined by nonlinear regression; inhibition models included competitive, mixed competitive-noncompetitive, and noncompetitive. Time-dependent inhibition was assessed with 20-min preincubation and additional preincubation times for CYP3A.
- Curcuminoid extract was analyzed by HPLC and contained 66% curcumin, 23% demethoxycurcumin, and 11% bisdemethoxycurcumin. Pure curcuminoids were synthesized and tested individually and as a mixture. Human liver microsomes from 50 individuals were pooled for UGT assays; individual high-activity livers were used for CYP assays; cytosol was pooled from four livers.
Limitations
- Stated: the study is in vitro, and controlled drug interaction studies in human subjects are warranted. The authors note that non-specific microsomal binding of curcuminoids was not evaluated and could lead to underestimation of inhibition potency; piperine plasma levels have not been reported; and it is not yet clear which UGT and SULT isozymes predominate in intestinal mucosa.
- Stated: predictions of intestinal interaction are based on expected tissue concentrations from oral dosing, not on measured human intestinal concentrations or clinical outcomes.
- Evident from the text: no in vivo human drug-interaction data are presented, and the relatively high acetaminophen concentration used (10 mM) may have minimized competitive inhibition by piperine.
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“CYP2C9 13.5 ± 1.4 40.7 ± 4.1 0.44 ± 0.03 Sulfaphenazole”
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“or inhibition of CYP3A activities by piperine (Figs. 3B-D).”
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“curcumin being the least potent inhibitor of HLC acetaminophen sulfation compared with the other curcuminoids, the pure mixture and the extract.”
plainstates a cause- Asserted: passes — The authors put it forward as true.
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“piperine at concentrations of up to 50 μM showed no inhibition of acetaminophen sulfation in either human liver cytosol or intact LS180 cells.”
plain- Asserted: passes — The authors put it forward as true.
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“All three curcuminoids had similar effects on CYP3A, UGT, and SULT activity”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the citing paper
“Alfentanil and cyclosporine are classified as narrow therapeutic index (NTI) drugs [36,37], as they are highly dependent on CYP3A for clearance.”
From Predicting Food–Drug Interactions between Piperine and CYP3A4 Substrate Drugs Using PBPK Modeling (2024) · cites this paper as [36]
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§ Results
“the effect of the individual synthetic curcuminoids on glucuronidation was similar to that of the curcuminoid mixture and curcuminoid extract (IC50 values ranged from 9.8 to 12.2 μM) except for curcumin”
§ Results
“UGT LS180 cells 12.1 ± 0.4 2.2 ± 0.1 13.9 ±2.3 9.8 ± 1.4 12.2 ± 1.8”
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In the paper
§ Discussion
“Inhibition of microsomal CYP3A activity by curcuminoids was both time-dependent (at substrate concentrations over 25 μM) and competitive.”
§ Results
“As shown in Fig. 3A, preincubation enhanced the effect of the curcuminoid extract on CYP3A activity at inhibitor concentrations over 25 μM.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Results
“the other synthetic curcuminoids, curcuminoid mixture and curcuminoid extract (5.6 to 9.6 μM)”
§ Results
“SULT LS180 cells 5.2 ± 0.6 2.6 ± 0.4 12.5 ± 0.4 5.6 ± 0.8 9.6 ± 1.4”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Results
“curcuminoid extract resulted in more than 4-fold greater inhibition of acetaminophen sulfation in liver fractions compared with intact LS180 cells with IC50 values of 5.2 ± 0.6 μM and 0.99 ± 0.04 μM, respectively”
§ Results
“SULT HLC 0.99 ± 0.04 5.9 ± 0.4 1.70 ± 0.06 0.95 ± 0.02 1.36 ± 0.06 SULT LS180 cells 5.2 ± 0.6 2.6 ± 0.4 12.5 ± 0.4 5.6 ± 0.8 9.6 ± 1.4”
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Metadata
- Authors
- Volak, L. P., Ghirmai, S., Cashman, J. R., & Court, M. H.
- Affiliations
- Tufts University (US)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 36
- Issue
- 8
- Pages
- 1594-1605
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC2574793
- OpenAlex
- W2118356995
- Cited by
- 214
- References
- 42
- Citations by year
- 2026: 27 · 2025: 20 · 2024: 7 · 2023: 7 · 2022: 11 · 2021: 20 · 2020: 15 · 2019: 8 · 2018: 11 · 2017: 8 · 2016: 13 · 2015: 10 · 2014: 14 · 2013: 8 · 2012: 14
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Pfizer UK
- National Institute of General Medical Sciences (R01GM061834, R21GM074369)
- National Center for Complementary and Integrative Health (F31AT003973)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Curcumin's Biomedical Applications
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- curcuminoids, piperine, herb-drug interactions, cytochrome P450 inhibition, CYP3A4, CYP2C9, CYP2C19, UDP-glucuronosyltransferase, sulfotransferase, curcumin, demethoxycurcumin, bisdemethoxycurcumin, enzyme inhibition kinetics
- MeSH terms
- Acetaminophen, Alkaloids, Chromatography, High Pressure Liquid, Curcumin, Enzyme Inhibitors, Humans, Liver, Piperidines, Recombinant Proteins, Spectrometry, Fluorescence, Spectrophotometry, Ultraviolet, Glucuronosyltransferase, Sulfotransferases, Spectrometry, Mass, Electrospray Ionization, Benzodioxoles, Polyunsaturated Alkamides, Cytochrome P-450 Enzyme Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-14, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-14 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
