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Research ArticleArticle

Characterization of Catechol Glucuronidation in Rat Liver

Laurence Antonio, Joël-Paul Grillasca, Jyrki Taskinen, Eivor Elovaara, Brian Burchell, Marie-Helene Piet, Brian Ethell, Mohamed Ouzzine, Sylvie Fournel-Gigleux and Jacques Magdalou
Drug Metabolism and Disposition February 2002, 30 (2) 199-207; DOI: https://doi.org/10.1124/dmd.30.2.199
Laurence Antonio
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Joël-Paul Grillasca
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Jyrki Taskinen
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Eivor Elovaara
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Brian Burchell
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Marie-Helene Piet
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Brian Ethell
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Mohamed Ouzzine
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Sylvie Fournel-Gigleux
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Jacques Magdalou
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Abstract

Catechols are a class of substances from natural or synthetic origin that contain a 1,2-dihydroxybenzene group. We have characterized the glucuronidation by rat liver microsomes and by the rat liver recombinant UDP-glucuronosyltransferase isoforms UGT1A6 and UGT2B1 of a series of 42 structurally diverse catechols, including neurotransmitters, polyphenols, drugs, and catechol estrogens. Small catechols (4-nitrocatechol, 2,3-dihydroxybenzaldehyde, 4-methylcatechol, and tetrachlorocatechol), tyrphostine A23, and octylgallate were glucuronidated at the highest rate by rat liver microsomes and the recombinant enzymes. By contrast, polyphenols from green tea (catechin and related compounds), 3,5-dinitrocatechol, the catechol-O-methyltransferase inhibitor drugs (entacapone, nitecapone, and tolcapone), the carboxyl catechols (gallic acid and dihydroxybenzoic acid derivatives), and the neurotransmitters and dopaminergic drugs, except dobutamine, were glucuronidated at low rate. Glucuronidation of most catechols was increased upon treatment of rats by 3-methylcholanthrene (3-MC) or Aroclor 1254. No induction was observed after administration of phenobarbital and clofibrate or treatment with catechols. Partial least-squares modeling was carried out to explain the variations of glucuronidation activity by liver microsomes of nontreated and 3-MC-treated rats. The model developed explained 82% and predicted 61% of the variations of glucuronidation activities. Among the 17 electronic and substructure parameters used that characterize the catechols, the hydrophobicity/molar volume ratio of catechols showed a strong positive correlation with the glucuronidation rate. The effect of the pKaof the catechol group was modeled to be nonlinear, the optimal pKa value for glucuronidation being between 8 and 9. Hydrogen bonding and steric effects also were important to account for to predict the glucuronidation rates.

Footnotes

  • ↵1 Current address: Biologie Moléculaire Marine, LCA, Département Génie Biologique, Universitéde Toulon et du Var, France.

  • This work was supported by the Commission of the European Communities Grant BMH4-CT97-2621 and by the Région Lorraine.

  • Abbreviations used are::
    COMT
    catechol-O-methyltransferase
    UGT
    UDP-glucuronosyltransferase
    PLS
    partial least squares
    3-MC
    3-methylcholanthrene
    HPLC
    high-performance liquid chromatography
    p
    proximal
    d
    distal
    o
    ortho
    RLM
    rat liver microsomes
    • Received June 21, 2001.
    • Accepted November 9, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (2)
Drug Metabolism and Disposition
Vol. 30, Issue 2
1 Feb 2002
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Research ArticleArticle

Characterization of Catechol Glucuronidation in Rat Liver

Laurence Antonio, Joël-Paul Grillasca, Jyrki Taskinen, Eivor Elovaara, Brian Burchell, Marie-Helene Piet, Brian Ethell, Mohamed Ouzzine, Sylvie Fournel-Gigleux and Jacques Magdalou
Drug Metabolism and Disposition February 1, 2002, 30 (2) 199-207; DOI: https://doi.org/10.1124/dmd.30.2.199

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Research ArticleArticle

Characterization of Catechol Glucuronidation in Rat Liver

Laurence Antonio, Joël-Paul Grillasca, Jyrki Taskinen, Eivor Elovaara, Brian Burchell, Marie-Helene Piet, Brian Ethell, Mohamed Ouzzine, Sylvie Fournel-Gigleux and Jacques Magdalou
Drug Metabolism and Disposition February 1, 2002, 30 (2) 199-207; DOI: https://doi.org/10.1124/dmd.30.2.199
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