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Cited by 88Pharmacogenetics and Drug MetabolismAlkaloids: synthesis and pharmacologyForensic Toxicology and Drug Analysis

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Evaluation of the Effects of Mitragyna speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay

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Kong, Wai Mun, Chik, Zamri, Ramachandra, Murali, Subramaniam, Umarani, Aziddin, Raja Elina Raja, Mohamed, Zahurin·2011·Molecules
DOI 10.3390/molecules16097344PMC PMC6264431
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Abstract

The extract from Mitragyna speciosa has been widely used as an opium substitute, mainly due to its morphine-like pharmacological effects. This study investigated the effects of M. speciosa alkaloid extract (MSE) on human recombinant cytochrome P450 (CYP) enzyme activities using a modified Crespi method. As compared with the liquid chromatography-mass spectrometry method, this method has shown to be a fast and cost-effective way to perform CYP inhibition studies. The results indicated that MSE has the most potent inhibitory effect on CYP3A4 and CYP2D6, with apparent half-maximal inhibitory concentration (IC50) values of 0.78 µg/mL and 0.636 µg/mL, respectively. In addition, moderate inhibition was observed for CYP1A2, with an IC50 of 39 µg/mL, and weak inhibition was detected for CYP2C19. The IC50 of CYP2C19 could not be determined, however, because inhibition was < 50%. Competitive inhibition was found for the MSE-treated CYP2D6 inhibition assay, whereas non-competitive inhibition was shown in inhibition assays using CYP3A4, CYP1A2 and CYP2C19. Quinidine (CYP2D6), ketoconazole (CYP3A4), tranylcypromine (CYP2C19) and furafylline (CYP1A2) were used as positive controls throughout the experiments. This study shows that MSE may contribute to an herb-drug interaction if administered concomitantly with drugs that are substrates for CYP3A4, CYP2D6 and CYP1A2.

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Figure 1 Percentage of inhibition of MSE on (a) CYP3A4; (b) CYP1A2; (c) CYP2D6; and (d) CYP2C19 activities after incubating at respective optimal incubation times. Two different concentrations (2 µM and 0.2 µM) of positive control (quinidine [CYP2D6], ketoconazole [CYP3A4], tranylcypromine [CYP2C19] and furafylline [CYP1A2]) were used throughout the assay.
Figure 1 Percentage of inhibition of MSE on (a) CYP3A4; (b) CYP1A2; (c) CYP2D6; and (d) CYP2C19 activities after incubating at respective optimal incubation times. Two different concentrations (2 µM and 0.2 µM) of positive control (quinidine [CYP2D6], ketoconazole [CYP3A4], tranylcypromine [CYP2C19] and furafylline [CYP1A2]) were used throughout the assay.CC BY · PubMed Central
Figure 2 Ki determination using the non-linear regression method. Direct plot reaction velocity against different concentrations of substrate in the absence or presence of different concentrations of Mitragyna speciosa extract. Increasing the M. speciosa extract concentration resulted in reduced apparent Vmax and increased apparent Km for CYP3A4, CYP1A2 and CYP2C19. For CYP2D6, Vmax remained constant but the Km value was increased (not shown).
Figure 2 Ki determination using the non-linear regression method. Direct plot reaction velocity against different concentrations of substrate in the absence or presence of different concentrations of Mitragyna speciosa extract. Increasing the M. speciosa extract concentration resulted in reduced apparent Vmax and increased apparent Km for CYP3A4, CYP1A2 and CYP2C19. For CYP2D6, Vmax remained constant but the Km value was increased (not shown).CC BY · PubMed Central
Figure 3 Dixon plot of substrate concentration/velocity (s/v) against i (M. speciosa extract) concentration for each of the substrate concentrations tested. The resulting lines intercept at a point corresponding to Ki. Each point was the mean of triplicate determinations.
Figure 3 Dixon plot of substrate concentration/velocity (s/v) against i (M. speciosa extract) concentration for each of the substrate concentrations tested. The resulting lines intercept at a point corresponding to Ki. Each point was the mean of triplicate determinations.CC BY · PubMed Central
Figure 4 Chemical structure of mitragynine and morphine.
Figure 4 Chemical structure of mitragynine and morphine.CC BY · PubMed Central

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Metadata

Authors
Kong, W. M., Chik, Z., Ramachandra, M., Subramaniam, U., Aziddin, R. E. R., & Mohamed, Z.
Affiliations
  • University of Malaya (MY)
  • Aurigene Discovery Technologies (India) (IN)
  • Aurigene Discovery Technologies (M) Sdn. Bhd, Malaysia, 57000 Bukit Jalil, Kuala Lumpur, Malaysia
  • Hospital Kuala Lumpur (MY)
Corresponding author
Kong, Wai Mun
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2011-08-29
Volume
16
Issue
9
Pages
7344-7356
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules16097344
PMC
PMC6264431
OpenAlex
W2122692346
Cited by
88
References
25
Citations by year
2026: 4 · 2025: 1 · 2024: 5 · 2023: 5 · 2022: 9 · 2021: 10 · 2020: 8 · 2019: 10 · 2018: 2 · 2017: 8 · 2016: 11 · 2015: 5 · 2014: 6 · 2013: 1 · 2012: 3
FWCI
3.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Universiti Malaya
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
Keywords
Mitragyna speciosa, kopi, alkaloid extract, cytochrome P450 inhibition, CYP3A4, CYP2D6, CYP1A2, CYP2C19, herb-drug interactions, competitive inhibition, non-competitive inhibition, high-throughput assay
MeSH terms
Alkaloids, Aryl Hydrocarbon Hydroxylases, Humans, Kinetics, Plant Extracts, Recombinant Proteins, Plant Leaves, Mitragyna, Enzyme Assays, High-Throughput Screening Assays

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