The DOI matches its Crossref record; 43 of the 44 references it cites were found in a registry or an index; none of the 19 sources its claims cite is checked for support yet.
Piperine Is a Mechanism-Based Inactivator of CYP3A
Open accessAbstract
Piperine (PPR) is the representative alkaloid component of the piper species (family: Piperaceae). Our rapid screening study found PPR caused time-dependent inhibition of cytochrome P450s (CYP) 3A and 2D6, and CYP3A was inactivated the most. Further study demonstrated that PPR is a time-, concentration-, and NADPH-dependent inhibitor of CYP3A, and significant loss (49.5% ± 3.9%) of CYP3A activity was observed after 20minute incubations with 80 μ M PPR at 37°C. The values of K I and k inact were 30.7 μ M and 0.041 minutes-1, respectively. CYP3A competitive inhibitor ketoconazole showed protective effect against the enzyme inactivation. Superoxide dismutase/catalase and GSH displayed minor protection against the PPR-caused enzyme inactivation. Ferricyanide partially reduced the enzyme inhibition by PPR. Additionally, NADPH-dependent formation of reactive metabolites from PPR were found in human liver microsomal incubation mixtures. An ortho-quinone intermediate was trapped by NAC in microsomal incubations with PPR. DM-PPR, demethylene metabolite of PPR, showed weak enzyme inactivation relative to that caused by PPR. It appears that both carbene and ortho-quinone intermediates were involved in the inactivation of CYP3A caused by PPR. SIGNIFICANCE STATEMENT: CYP3A subfamily members (mainly CYP3A4 and CYP3A5) play a critical role in drug metabolism. Piperine (PPR), a methylenedioxyphenyl derivative combined with an unsaturated ketone, is the major active ingredient of pepper. PPR revealed time-, concentration-, and NADPH-dependent inhibitory effect on CYP3A. Carbene and quinone metabolites were both involved in the observed CYP3A inactivation by PPR. Apparently, the unsaturated ketone moiety did not participate in the enzyme inactivation. The present study sounds an alert of potential risk for food-drug interactions.
Overview
CoChat Summary
TL;DR
Piperine (PPR) is a time-, concentration-, and NADPH-dependent inactivator of CYP3A in human liver microsomes, with both carbene and ortho-quinone metabolites implicated. It also causes time-dependent inhibition of CYP2D6 and raises potential food-drug interaction concerns.
Key findings
- Rapid screening showed PPR (80 µM) caused time-dependent loss of CYP3A and CYP2D6; after 20 minutes, remaining activities were about 50% and 57%, respectively, with CYP3A inactivated the most. CYP3A activity loss was 49.5% ± 3.9% after 20-minute incubations with 80 µM PPR at 37°C; K_I = 30.7 µM and k_inact = 0.041 min⁻¹.
- Ketoconazole protected against CYP3A inactivation: residual CYP3A activity at 20 minutes was 47.9% ± 5.2% without ketoconazole versus 59.3% ± 0.7%, 71.6% ± 1.9%, and 81.0% ± 1.3% with 0.01, 0.1, and 1.0 µM ketoconazole, respectively. GSH and SOD/catalase showed minor or little protection.
- The partition ratio was approximately 273. Dialysis restored CYP3A activity from 28.2% ± 3.2% predialysis to 71.9% ± 5.2% postdialysis (43.7% recovery), and ferricyanide recovered 39.7% of CYP3A activity. DM-PPR caused weaker inactivation (31.8% ± 2.5% loss) than PPR (50.3% ± 2.7% loss) at 80 µM over 20 minutes.
- NAC trapping identified eight conjugates (M1–M8), including an ortho-quinone intermediate; CYP1A2 was the major enzyme participating in formation of M3–M8. Both carbene and ortho-quinone intermediates were involved in CYP3A inactivation, while the unsaturated ketone moiety apparently did not participate.
Methods
- In vitro studies used human liver microsomes and recombinant human CYP enzymes with probe substrates and LC-MS/MS to measure CYP activities; experiments assessed time-, concentration-, and NADPH-dependent inhibition of CYP3A and effects of ketoconazole, GSH, SOD/catalase, ferricyanide, dialysis, and partition ratio.
- Reactive metabolites were characterized by NAC trapping, LC-MS/MS, chemical synthesis of DM-PPR and NAC conjugates, and incubations with individual recombinant P450 enzymes plus selective P450 inhibitors to identify bioactivation enzymes.
- Data are reported as mean ± S.D. (n = 3), with statistical comparisons by unpaired t test and significance at P < 0.05, P < 0.01, or P < 0.001.
Limitations
- Stated: poor reaction yield and heavy impurity with similar retention time prevented obtaining sufficient amounts of individual products for NMR characterization; whether PPR is a mechanism-based inactivator of CYP2D6 needs further investigation.
- Evident from the text: all experiments are in vitro using human liver microsomes or recombinant enzymes, so clinical or in vivo food-drug interaction risk is not directly demonstrated.
- Evident from the text: no human subject or in vivo pharmacokinetic data are reported, and CYP2D6 inactivation is not fully characterized.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
0 Valid · 0 Not valid · 14 Not checked · 67 Own results and interpretations
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PPR was found to cause time-, concentration-, and NADPHdependent inhibition of CYP3A (Fig. 2, A and B).”
§ Piperine Is a Mechanism-Based Inactivator of CYP3A s > Discussion
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SOD and catalase, scavengers of ROS, displayed little protective effect on the inactivation of CYP3A”
§ Piperine Is a Mechanism-Based Inactivator of CYP3A s > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The signals responsible for the methylene moiety observed in the 1 H NMR spectrum of the parent compound disappeared in the spectrum of the product.”
§ Piperine Is a Mechanism-Based Inactivator of CYP3A s > Reversibility of Inactivation.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, NADPH-dependent formation of reactive metabolites from PPR were found in human liver microsomal incubation mixtures.”
§ Piperine Is a Mechanism-Based Inactivator of CYP3A s > Abstract
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“M1-M8 were all observed in the synthetic mixture by LC-MS/MS.”
§ Piperine Is a Mechanism-Based Inactivator of CYP3A s > Reversibility of Inactivation.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
48 more claims
Create a free account to see all 81 claims and to verify the 19 references still open.
- It may state two separate claims as one. 20
- The quote only partly states this claim. 1
- Probably not a substantial claim. 15
Citations
Cites
Rendic, S., & Carlo, F. J. D. (1997) · Drug Metabolism Reviews · doi:10.3109/03602539709037591 · Cited by 949
Inhibition and Induction of Cytochrome P450 and the Clinical Implications
Lin, J. H., & Lu, A. Y. H. (1998) · Clinical Pharmacokinetics · doi:10.2165/00003088-199835050-00003 · Cited by 829
Bang, J. S., Oh, D. H., Choi, H. M., Sur, B., Lim, S., Kim, J. Y., Yang, H.-I., Yoo, M. C., Hahm, D., & Kim, K. S. (2009) · Arthritis Research & Therapy · doi:10.1186/ar2662 · Cited by 416
Mixed-function oxidase involvement in the biochemistry of insecticide synergists
Casida, J. E. (1970) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf60171a013 · Cited by 380
Chonpathompikunlert, P., Wattanathorn, J., & Muchimapura, S. (2010) · Food and Chemical Toxicology · doi:10.1016/j.fct.2009.12.009 · Cited by 291
Zarai, Z., Boujelbene, E., Ben Salem, N., Gargouri, Y., & Sayari, A. (2013) · LWT - Food Science and Technology · doi:10.1016/j.lwt.2012.07.036 · Cited by 266
Ono, S., Hatanaka, T., Hotta, H., Satoh, T., Gonzalez, F. J., & Tsutsui, M. (1996) · Xenobiotica · doi:10.3109/00498259609046742 · Cited by 233
Analgesic and anti-inflammatory activities of Piper nigrum L.
Tasleem, F., Azhar, I., Ali, S. N., Perveen, S., & Mahmood, Z. (2014) · Asian Pacific Journal of Tropical Medicine · doi:10.1016/s1995-7645(14)60275-3 · Cited by 203
Kumar, A., Khan, I. A., Koul, S., Koul, J. L., Taneja, S. C., Ali, I., Ali, F. H. M., Sharma, S., Mirza, Z. M., Kumar, M. S., et al. (2008) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkn088 · Cited by 173
An Ayurvedic formulation ‘Trikatu’ and its constituents
Johri, R. K., & Zutshi, U. (1992) · Journal of Ethnopharmacology · doi:10.1016/0378-8741(92)90067-2 · Cited by 163
Ohnishi, A., Matsuo, H., Yamada, S., Takanaga, H., Morimoto, S., Shoyama, Y., Ohtani, H., & Sawada, Y. (2000) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703433 · Cited by 162
Co-delivery of rapamycin- and piperine-loaded polymeric nanoparticles for breast cancer treatment
Katiyar, S. S., Muntimadugu, E., Rafeeqi, T. A., Domb, A. J., & Khan, W. (2015) · Drug Delivery · doi:10.3109/10717544.2015.1039667 · Cited by 153
Piperine, the potential functional food for mood and cognitive disorders
Wattanathorn, J., Chonpathompikunlert, P., Muchimapura, S., Priprem, A., & Tankamnerdthai, O. (2008) · Food and Chemical Toxicology · doi:10.1016/j.fct.2008.06.014 · Cited by 149
Murray, G. I., Barnes, T., Hf, S., Ewen, S. W. B., Melvin, W., & Burke, M. D. (1988) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1988.tb03331.x · Cited by 146
Murray, M. (2000) · Current Drug Metabolism · doi:10.2174/1389200003339270 · Cited by 145
Samra, Y. A., Said, H. S., Elsherbiny, N. M., Liou, G. I., El‐Shishtawy, M. M., & Eissa, L. A. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.06.002 · Cited by 135
Inhibition of lipopolysaccharide-induced inflammatory responses by piperine
Bae, G., Kim, M., Jung, W., Seo, S.-W., Yun, S.-W., Kim, S. G., Park, R., Kim, E.-C., Song, H., & Park, S. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.05.026 · Cited by 119
Gupta, R. A., Motiwala, M. N., Dumore, N. G., Danao, K. R., & Ganjare, A. B. (2015) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2015.01.039 · Cited by 118
Mechanism-based inactivators as probes of cytochrome P450 structure and function
Kent, U., Jushchhyshyn, M., & Hollenberg, P. (2001) · Current Drug Metabolism · doi:10.2174/1389200013338478 · Cited by 113
Umar, S., Golam Sarwar, A. H. M., Umar, K., Ahmad, N., Sajad, M., Ahmad, S., Katiyar, C. K., & Khan, H. A. (2013) · Cellular Immunology · doi:10.1016/j.cellimm.2013.07.004 · Cited by 107
The analgesic and anticonvulsant effects of Piperine in mice
Al-Humayyd, M. S., Bukhari, I. A., Mahesar, A. L., & Gilani, A. H. (2013) · The FASEB Journal · doi:10.1096/fasebj.27.1_supplement.660.5 · Cited by 88
The analgesic and anticonvulsant effects of piperine in mice.
Bukhari, I. A., Pivac, N., Alhumayyd, M. S., Mahesar, A. L., & Gilani, A. H. (2013) · PubMed · Cited by 76
Usia, T., Watabe, T., Kadota, S., & Tezuka, Y. (2005) · Life Sciences · doi:10.1016/j.lfs.2004.12.005 · Cited by 74
Synthesis, anticancer and antibacterial activities of piperine analogs
Umadevi, P., Kolli, D., & Venugopal, D. V. R. (2013) · Medicinal Chemistry Research · doi:10.1007/s00044-013-0541-4 · Cited by 70
Parkinson, A., Kazmi, F., Buckley, D. B., Yerino, P., Paris, B. L., Holsapple, J., Toren, P., Otradovec, S. M., & Ogilvie, B. W. (2011) · Drug Metabolism and Disposition · doi:10.1124/dmd.111.038596 · Cited by 67
Watanabe, A., Nakamura, K., Okudaira, N., Okazaki, O., & Sudo, K.-I. (2007) · Drug Metabolism and Disposition · doi:10.1124/dmd.107.015016 · Cited by 66
Identification of epoxybergamottin as a CYP3A4 inhibitor in grapefruit peel
Wangensteen, H., Molden, E., Christensen, H., & Malterud, K. E. (2003) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-002-0537-3 · Cited by 62
Anti-inflammatory Effect of Piperine in Adjuvant-Induced Arthritic Rats—a Biochemical Approach
Murunikkara, V., Pragasam, S. J., Kodandaraman, G., Prince, S. E., & Rasool, M. (2012) · Inflammation · doi:10.1007/s10753-012-9448-3 · Cited by 53
Kahan, E., Kahan, N. R., & CHINITZ, D. P. (2003) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-003-0673-4 · Cited by 46
Taxak, N., Patel, B., & Bharatam, P. V. (2013) · Inorganic Chemistry · doi:10.1021/ic400010d · Cited by 44
Yang, A., He, X., Chen, J.-X., He, L.-N., Jin, C., Wang, L., Zhang, F., & An, L. (2015) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2015.06.018 · Cited by 41
Mechanism-Based Inactivation of Cytochrome P450 3A4 by 4-Ipomeanol
Alvarez-Diez, T. M., & Zheng, J. (2004) · Chemical Research in Toxicology · doi:10.1021/tx034143l · Cited by 40
Self-citationInhibition of cytochrome P450 3A4 by a pyrimidineimidazole: evidence for complex heme interactions
Hutzler, J. M., Melton, R. J., Rumsey, J. M., Schnute, M. E., Locuson, C. W., & Wienkers, L. C. (2006) · Chemical Research in Toxicology · doi:10.1021/tx060198m · Cited by 38
Assessment of drug-drug interactions caused by metabolism-dependent cytochrome P450 inhibition
Lee, J.-Y., Lee, S. Y., Oh, S. J., Lee, K. H., Jung, Y. S., & Kim, S. K. (2012) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2012.05.007 · Cited by 38
SKF 525-A inhibition, induction, and 452-nm complex formation
Buening, M. K., & Franklin, M. R. (1976) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)06011-8 · Cited by 37
Inactivation of Human Cytochrome P450 3A4 and 3A5 by Dronedarone and N-Desbutyl Dronedarone
Hong, Y., Chia, Y. M. F., Yeo, R. H., Venkatesan, G., Koh, S. K., Chai, C. L. L., Zhou, L., Kojodjojo, P., & Chan, E. C. Y. (2015) · Molecular Pharmacology · doi:10.1124/mol.115.100891 · Cited by 35
Piperine ameliorates collagenase-induced Achilles tendon injury in the rat
Gong, F., Cui, L., Zhang, X., Zhan, X., Gong, X., & Wen, Y. L. (2017) · Connective Tissue Research · doi:10.1080/03008207.2017.1289188 · Cited by 22
Rao, V. R. S., Suresh, G., Rao, R. R., Babu, K. S., Chashoo, G., Saxena, A. K., & Rao, J. M. (2010) · Medicinal Chemistry Research · doi:10.1007/s00044-010-9500-5 · Cited by 20
Moruno-Dávila, M. A., Garrido-del Solo, C., Garcı́a-Moreno, M., Havsteen, B. H., Garcia-Sevilla, F., Garcia-Cánovas, F., & Varón, R. (2001) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(00)00076-5 · Cited by 16
Assessment of the metabolism and intrinsic reactivity of a novel catechol metabolite
Hutzler, J. M., Melton, R. J., Rumsey, J. M., Thompson, D. C., Rock, D. A., & Wienkers, L. C. (2008) · Chemical Research in Toxicology · doi:10.1021/tx700429v · Cited by 16
Reversal of the effects of isoniazid on hepatic cytochrome P-450 by potassium ferricyanide
Muakkassah-Kelly, S. F., Bidlack, W. R., & Yang, W. C. (1982) · Biochemical Pharmacology · doi:10.1016/0006-2952(82)90218-0 · Cited by 15
Salminen, K. A., Meyer, A., Imming, P., & Raunio, H. (2011) · Drug Metabolism and Disposition · doi:10.1124/dmd.111.041319 · Cited by 15
(2010) · PubMed
Cited by
Piperine: A review of its biological effects
Haq, I., Imran, M., Nadeem, M., Tufail, T., Gondal, T. A., & Mubarak, M. S. (2021) · Phytotherapy Research · doi:10.1002/ptr.6855 · Cited by 434
Heidari, H., Bagherniya, M., Majeed, M. A., Sathyapalan, T., Jamialahmadi, T., & Sahebkar, A. (2023) · Phytotherapy Research · doi:10.1002/ptr.7737 · Cited by 195
Cancer chemoprevention: signaling pathways and strategic approaches
Ren, J., Yan, G., Yang, L., Kong, L., Guan, Y., Sun, H., Liu, C., Liu, L., Han, Y., & Wang, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02167-1 · Cited by 75
Yu, D.-N., Kan, Z., Shan, F., Zang, J., & Zhou, J. (2020) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.0c00443 · Cited by 67
Piperine and Its Metabolite’s Pharmacology in Neurodegenerative and Neurological Diseases
Azam, S., Park, J., Kim, I., & Choi, D. (2022) · Biomedicines · doi:10.3390/biomedicines10010154 · Cited by 64
Metadata
- Authors
- Cui, T., Wang, Q., Tian, X., Zhang, K., Peng, Y., & Zheng, J.
- Affiliations
- Shenyang Pharmaceutical University (CN)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 48
- Issue
- 2
- Pages
- 123-134
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2990432456
- Cited by
- 37
- References
- 44
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 2 · 2020: 3
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81430086, 81830104, 81773813], U1812403)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Piperaceae Chemical and Biological Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- piperine, CYP3A, mechanism-based inhibition, carbene intermediates, food-drug interactions, reactive metabolites, CYP3A4, CYP3A5
- MeSH terms
- Alkaloids, Catalase, Enzyme Inhibitors, Humans, Ketoconazole, Kinetics, Metabolic Clearance Rate, Microsomes, Liver, NADP, Piperidines, Superoxide Dismutase, Cytochrome P-450 CYP3A, Benzodioxoles, Polyunsaturated Alkamides, Cytochrome P-450 CYP3A 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 ›
Are you an author, or do you see a problem with this page? Request a review
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.
