Characterization of human hepatic and extrahepatic UDP- glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids

Anna Mazur, Cheryl F. Lichti, Paul L. Prather, Agnieszka K. Zielinska, Stacie M. Bratton, Anna Gallus-Zawada, Moshe Finel, Grover P. Miller, Anna Radomińska-Pandya, Jeffery H. Moran

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Tetrahydrocannabinol (Δ9-THC), the primary psychoactive ingredient in marijuana, is subject to cytochrome P450 oxidation and subsequent UDP-glucuronosyltransferase (UGT)-dependent glucuronidation. Many studies have shown that CYP2C9 and CYP3A4 are the primary enzymes responsible for these cytochrome P450-dependent oxidations, but little work has been done to characterize phase II metabolic pathways. In this study, we test the hypothesis that there are specific human UGTs responsible for classic cannabinoid metabolism. The activities of 12 human recombinant UGTs toward classic cannabinoids [cannabinol (CBN), cannabidiol (CBD), (-)-Δ8-THC, (-)-Δ9-THC, (±)-11-hydroxy-Δ9-THC (THC-OH), and (-)-11-nor-9-carboxy-Δ9-THC (THC-COOH)] were evaluated using high-performance liquid chromatography-tandem mass spectrometry and labeling assays. Despite activity by UGT1A1, 1A3, 1A8, 1A9, 1A10, and 2B7 toward CBN, CBD, THC-OH, and THC-COOH, only selected UGTs demonstrate sufficient activity for further characterization of steady-state kinetics. CBN was the most recognized substrate as evidenced by activities from hepatic UGT1A9 and extrahepatic UGT1A7, UGT1A8, and UGT1A10. These results may reflect the introduction of an aromatic ring to Δ9-THC, leading to favorable π stacking with phenylalanines in the UGT active site. Likewise, oxidation of Δ9-THC to THC-OH results in UGT1A9 and UGT1A10 activity toward the cannabinoid. Further oxidation to THC-COOH surprisingly leads to a loss in metabolism by UGT1A9 and UGT1A10, while creating a substrate recognized by UGT1A1 and UGT1A3. The resulting glucuronide of THC-COOH is the main metabolite found in urine, and thus these hepatic enzymes play a critical role in the metabolic clearance of cannabinoids. Taken together, glucuronidation of cannabinoids depends on upstream processing including enzymes such as CYP2C9 and CYP3A4.

Original languageEnglish (US)
Pages (from-to)1496-1504
Number of pages9
JournalDrug Metabolism and Disposition
Volume37
Issue number7
DOIs
StatePublished - Jul 2009
Externally publishedYes

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Glucuronosyltransferase
Dronabinol
Cannabinoids
Liver
Enzymes
Cannabinol
Cannabidiol
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System
Glucuronides
Cannabis
Tandem Mass Spectrometry
Metabolic Networks and Pathways
Phenylalanine
Human Activities

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Mazur, A., Lichti, C. F., Prather, P. L., Zielinska, A. K., Bratton, S. M., Gallus-Zawada, A., ... Moran, J. H. (2009). Characterization of human hepatic and extrahepatic UDP- glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids. Drug Metabolism and Disposition, 37(7), 1496-1504. https://doi.org/10.1124/dmd.109.026898

Characterization of human hepatic and extrahepatic UDP- glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids. / Mazur, Anna; Lichti, Cheryl F.; Prather, Paul L.; Zielinska, Agnieszka K.; Bratton, Stacie M.; Gallus-Zawada, Anna; Finel, Moshe; Miller, Grover P.; Radomińska-Pandya, Anna; Moran, Jeffery H.

In: Drug Metabolism and Disposition, Vol. 37, No. 7, 07.2009, p. 1496-1504.

Research output: Contribution to journalArticle

Mazur, A, Lichti, CF, Prather, PL, Zielinska, AK, Bratton, SM, Gallus-Zawada, A, Finel, M, Miller, GP, Radomińska-Pandya, A & Moran, JH 2009, 'Characterization of human hepatic and extrahepatic UDP- glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids', Drug Metabolism and Disposition, vol. 37, no. 7, pp. 1496-1504. https://doi.org/10.1124/dmd.109.026898
Mazur, Anna ; Lichti, Cheryl F. ; Prather, Paul L. ; Zielinska, Agnieszka K. ; Bratton, Stacie M. ; Gallus-Zawada, Anna ; Finel, Moshe ; Miller, Grover P. ; Radomińska-Pandya, Anna ; Moran, Jeffery H. / Characterization of human hepatic and extrahepatic UDP- glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids. In: Drug Metabolism and Disposition. 2009 ; Vol. 37, No. 7. pp. 1496-1504.
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