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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
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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.
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“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
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“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
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“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.
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“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
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“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.
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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
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