Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle
Open Access

Inhibition of UDP-Glucuronosyltransferase Enzymes by Major Cannabinoids and Their Metabolites

Shamema Nasrin, Christy J. W. Watson, Keti Bardhi, Gabriela Fort, Gang Chen and Philip Lazarus
Drug Metabolism and Disposition December 2021, 49 (12) 1081-1089; DOI: https://doi.org/10.1124/dmd.121.000530
Shamema Nasrin
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christy J. W. Watson
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Keti Bardhi
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gabriela Fort
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gang Chen
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip Lazarus
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Article Figures & Data

Figures

  • Tables
  • Additional Files
  • Fig. 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 1.

    Metabolic pathways and structures of major cannabinoids and their metabolites.

  • Fig. 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 2.

    Chromatograms of probe metabolites in microsomes from UGT-overexpressing HEK293 cell lines. Probe substrates (at concentrations close to their known Km; see Supplemental Table 1) were incubated in rUGTs for 60–120 minutes at 37°C, and individual corresponding metabolites were analyzed by UPLC-MS/MS as described in Supplemental Table 1 and in the Materials and Methods.

  • Fig. 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 3.

    Screening of cannabinoid inhibition of major hepatic UGTs in microsomes from UGT-overexpressing HEK293 cell lines. Probe substrates were β-estradiol for UGT1A1, chenodeoxycholic acid for UGT1A3, trifluoperazine for UGT1A4, serotonin for UGT1A6, propofol for UGT1A9, codeine for UGT2B4, zidovudine for UGT2B7, nicotine for UGT2B10, oxazepam for UGT2B15, and dihydroexemestane for UGT2B17. Incubations were performed using 10 or 100 µM of cannabinoid, with probe substrate concentrations at or close to their known Km for their corresponding enzyme (see Supplemental Table 1). Shown are the mean inhibition of two individual experiments performed for each probe substrate. Data are expressed as a percentage of metabolite formation formed in assays with cannabinoid compared with assays without cannabinoid.

  • Fig. 4.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 4.

    Inhibitory effects of CBD on the glucuronidation of UGT probe substrates in microsomes from UGT-overexpressing HEK293 cell lines (rUGT), HLMs, and HKMs. Shown are representative plots comparing CBD concentration with the percent glucuronidation activity against probe substrates in rUGT microsomes, HLMs, and HKMs. Incubations were performed for 60–120 minutes at 37°C using 80–90 µg of rUGT microsomes or 90–200 µg HLMs or HKMs with the following probe substrates: propofol, acetaminophen, and furosemide for UGT1A9; serotonin for UGT1A6; codeine for UGT2B4; and AZT for UGT2B7 (see Supplemental Table 1 for concentrations). Individual metabolites were analyzed by UPLC-MS/MS as described in the Materials and Methods.

Tables

  • Figures
  • Additional Files
    • View popup
    TABLE 1

    IC50 values (µM) of cannabinoids against major hepatic UGT enzymes in microsomes from recombinant UGT–overexpressing cells, HLMs, or HKMs.

    Probe substrateMicrosomesTHCCBDCBN
    IC50IC50,uIC50IC50,uIC50IC50,u
    µMµMµMµMµMµM
    SerotoninrUGT1A610 ± 2.60.40 ± 0.10
    HKMNA17 ± 3.71.0 ± 0.23NA
    HLM28 ± 6.51.4 ± 0.33
    CodeinerUGT2B411 ± 2.70.47 ± 0.115.8 ± 1.20.22 ± 0.045
    HKM55 ± 5.22.9 ± 0.2739 ± 5.92.5 ± 0.37NA
    HLM13 ± 2.60.61 ± 0.138.0 ± 1.10.40 ± 0.058
    AZTrUGT2B733 ± 8.51.4 ± 0.3621 ± 3.90.82 ± 0.1549 ± 124.2 ± 1.1
    HKM51 ± 122.6 ± 0.6535 ± 3.52.2 ± 0.2257 ± 7.56.9 ± 0.90
    HLM59 ± 6.62.8 ± 0.3230 ± 4.11.5 ± 0.2159 ± 8.65.5 ± 0.79
    PropofolrUGT1A911 ± 3.00.45 ± 0.123.2 ± 0.520.12 ± 0.0206.0 ± 0.750.51 ± 0.063
    HKM12 ± 3.40.64 ± 0.185.5 ± 0.560.34 ± 0.0357.5 ± 1.70.90 ± 0.20
    HLM30 ± 6.41.4 ± 0.3119 ± 4.61.0 ± 0.2431 ± 4.12.9 ± 0.38
    FurosemiderUGT1A98.0 ± 0.470.33 ± 0.0202.4 ± 0.660.090 ± 0.0259.2 ± 2.10.78 ± 0.18
    HKM10 ± 4.10.54 ± 0.223.6 ± 0.800.22 ± 0.04915 ± 0.771.9 ± 0.092
    HLM32 ± 6.31.5 ± 0.3029 ± 4.01.5 ± 0.2034 ± 6.33.1 ± 0.58
    AcetaminophenrUGT1A912 ± 3.70.49 ± 0.151.9 ± 0.290.073 ± 0.0116.9 ± 0.540.59 ± 0.046
    HKM15 ± 3.00.79 ± 0.163.8 ± 0.820.24 ± 0.0521 ± 3.42.6 ± 0.41
    HLM29 ± 8.91.4 ± 0.4312 ± 3.20.64 ± 0.1630 ± 4.52.8 ± 0.96
    • IC50 values are presented as means ± S.D. of three independent experiments. IC50,u, binding-corrected IC50; NA, not analyzed.

Additional Files

  • Figures
  • Tables
  • Data Supplement

    • Supplemental Data -

      Supplemental Table 1. Assay conditions used for the experiments.

      Supplemental Figure 1. Inhibitory effects of THC and CBN on the glucuronidation of UGT probe substrates in microsomes from UGT-overexpressing HEK293 cell lines (rUGT), HLM and HKM.

PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 49 (12)
Drug Metabolism and Disposition
Vol. 49, Issue 12
1 Dec 2021
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Inhibition of UDP-Glucuronosyltransferase Enzymes by Major Cannabinoids and Their Metabolites
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Cannabinoids and Their Metabolites as UGT Enzyme Inhibitors

Shamema Nasrin, Christy J. W. Watson, Keti Bardhi, Gabriela Fort, Gang Chen and Philip Lazarus
Drug Metabolism and Disposition December 1, 2021, 49 (12) 1081-1089; DOI: https://doi.org/10.1124/dmd.121.000530

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Cannabinoids and Their Metabolites as UGT Enzyme Inhibitors

Shamema Nasrin, Christy J. W. Watson, Keti Bardhi, Gabriela Fort, Gang Chen and Philip Lazarus
Drug Metabolism and Disposition December 1, 2021, 49 (12) 1081-1089; DOI: https://doi.org/10.1124/dmd.121.000530
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Material and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Series-Compartment Models of Hepatic Elimination
  • Warfarin PBPK Model with TMDD Mechanism
  • Identification of payload-containing catabolites of ADCs
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics