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Research ArticleArticle

Glucuronidation of Psilocin and 4-Hydroxyindole by the Human UDP-Glucuronosyltransferases

Nenad Manevski, Mika Kurkela, Camilla Höglund, Timo Mauriala, Michael H. Court, Jari Yli-Kauhaluoma and Moshe Finel
Drug Metabolism and Disposition March 2010, 38 (3) 386-395; DOI: https://doi.org/10.1124/dmd.109.031138
Nenad Manevski
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Mika Kurkela
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Camilla Höglund
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Timo Mauriala
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Michael H. Court
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Jari Yli-Kauhaluoma
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Moshe Finel
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Abstract

We have examined the glucuronidation of psilocin, a hallucinogenic indole alkaloid, by the 19 recombinant human UDP-glucuronosyltransferases (UGTs) of subfamilies 1A, 2A, and 2B. The glucuronidation of 4-hydroxyindole, a related indole that lacks the N,N-dimethylaminoethyl side chain, was studied as well. UGT1A10 exhibited the highest psilocin glucuronidation activity, whereas the activities of UGTs 1A9, 1A8, 1A7, and 1A6 were significantly lower. On the other hand, UGT1A6 was by far the most active enzyme mediating 4-hydroxyindole glucuronidation, whereas the activities of UGTs 1A7–1A10 toward 4-hydroxyindole resembled their respective psilocin glucuronidation rates. Psilocin glucuronidation by UGT1A10 followed Michaelis-Menten kinetics in which psilocin is a low-affinity high-turnover substrate (Km = 3.8 mM; Vmax = 2.5 nmol/min/mg). The kinetics of psilocin glucuronidation by UGT1A9 was more complex and may be best described by biphasic kinetics with both intermediate (Km1 = 1.0 mM) and very low affinity components. The glucuronidation of 4-hydroxyindole by UGT1A6 exhibited higher affinity (Km = 178 μM) and strong substrate inhibition. Experiments with human liver and intestinal microsomes (HLM and HIM, respectively) revealed similar psilocin glucuronidation activity in both samples, but a much higher 4-hydroxyindole glucuronidation rate was found in HLM versus HIM. The expression levels of UGTs 1A6–1A10 in different tissues were studied by quantitative real-time-PCR, and the results, together with the activity assays findings, suggest that whereas psilocin may be subjected to extensive glucuronidation by UGT1A10 in the small intestine, UGT1A9 is likely the main contributor to its glucuronidation once it has been absorbed into the circulation.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM061834] (to M.H.C.); the Academy of Finland [Grant 120975] (to J.Y.-K.); the Research Foundation of the University of Helsinki (to N.M.); and the Sigrid Juselius Foundation (to M.F.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.031138.

  • LC-MS
    liquid chromatography-mass spectrometry
    UGT
    UDP-glucuronosyltransferase
    UDPGA
    UDP-α-d-glucuronic acid
    HLM
    human liver microsomes
    CAS
    Chemical Abstract Service
    DTT
    dl-dithiothreitol
    HPLC
    high-performance liquid chromatography
    HIM
    human intestinal microsomes
    UPLC
    ultraperformance liquid chromatography
    DMSO
    dimethyl sulfoxide
    qRT-PCR
    quantitative real-time PCR.

    • Received November 10, 2009.
    • Accepted December 10, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (3)
Drug Metabolism and Disposition
Vol. 38, Issue 3
1 Mar 2010
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Research ArticleArticle

Glucuronidation of Psilocin and 4-Hydroxyindole by the Human UDP-Glucuronosyltransferases

Nenad Manevski, Mika Kurkela, Camilla Höglund, Timo Mauriala, Michael H. Court, Jari Yli-Kauhaluoma and Moshe Finel
Drug Metabolism and Disposition March 1, 2010, 38 (3) 386-395; DOI: https://doi.org/10.1124/dmd.109.031138

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Research ArticleArticle

Glucuronidation of Psilocin and 4-Hydroxyindole by the Human UDP-Glucuronosyltransferases

Nenad Manevski, Mika Kurkela, Camilla Höglund, Timo Mauriala, Michael H. Court, Jari Yli-Kauhaluoma and Moshe Finel
Drug Metabolism and Disposition March 1, 2010, 38 (3) 386-395; DOI: https://doi.org/10.1124/dmd.109.031138
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