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Research ArticleArticles

Involvement of UDP-Glucuronosyltransferases UGT1A9 and UGT2B7 in Ethanol Glucuronidation, and Interactions with Common Drugs of Abuse

Alaa Al Saabi, Delphine Allorge, François-Ludovic Sauvage, Gilles Tournel, Jean-michel Gaulier, Pierre Marquet and Nicolas Picard
Drug Metabolism and Disposition March 2013, 41 (3) 568-574; DOI: https://doi.org/10.1124/dmd.112.047878
Alaa Al Saabi
EA4483, Faculty of Medicine, Université Lille-Nord de France, Lille, France (A.A.S., D.A., G.T.); Centre Hospitalier Régional Universitaire de Lille, Laboratory of Toxicology, Lille, France (A.A.S., D.A.); INSERM, Unité Mixte de Recherche S-850, Limoges, France (A.A.S., F.-L.S., P.M., N.P.); and CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France (F.-L.S., J.-m.G., P.M., N.P.)
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Delphine Allorge
EA4483, Faculty of Medicine, Université Lille-Nord de France, Lille, France (A.A.S., D.A., G.T.); Centre Hospitalier Régional Universitaire de Lille, Laboratory of Toxicology, Lille, France (A.A.S., D.A.); INSERM, Unité Mixte de Recherche S-850, Limoges, France (A.A.S., F.-L.S., P.M., N.P.); and CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France (F.-L.S., J.-m.G., P.M., N.P.)
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François-Ludovic Sauvage
EA4483, Faculty of Medicine, Université Lille-Nord de France, Lille, France (A.A.S., D.A., G.T.); Centre Hospitalier Régional Universitaire de Lille, Laboratory of Toxicology, Lille, France (A.A.S., D.A.); INSERM, Unité Mixte de Recherche S-850, Limoges, France (A.A.S., F.-L.S., P.M., N.P.); and CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France (F.-L.S., J.-m.G., P.M., N.P.)
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Gilles Tournel
EA4483, Faculty of Medicine, Université Lille-Nord de France, Lille, France (A.A.S., D.A., G.T.); Centre Hospitalier Régional Universitaire de Lille, Laboratory of Toxicology, Lille, France (A.A.S., D.A.); INSERM, Unité Mixte de Recherche S-850, Limoges, France (A.A.S., F.-L.S., P.M., N.P.); and CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France (F.-L.S., J.-m.G., P.M., N.P.)
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Jean-michel Gaulier
EA4483, Faculty of Medicine, Université Lille-Nord de France, Lille, France (A.A.S., D.A., G.T.); Centre Hospitalier Régional Universitaire de Lille, Laboratory of Toxicology, Lille, France (A.A.S., D.A.); INSERM, Unité Mixte de Recherche S-850, Limoges, France (A.A.S., F.-L.S., P.M., N.P.); and CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France (F.-L.S., J.-m.G., P.M., N.P.)
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Pierre Marquet
EA4483, Faculty of Medicine, Université Lille-Nord de France, Lille, France (A.A.S., D.A., G.T.); Centre Hospitalier Régional Universitaire de Lille, Laboratory of Toxicology, Lille, France (A.A.S., D.A.); INSERM, Unité Mixte de Recherche S-850, Limoges, France (A.A.S., F.-L.S., P.M., N.P.); and CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France (F.-L.S., J.-m.G., P.M., N.P.)
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Nicolas Picard
EA4483, Faculty of Medicine, Université Lille-Nord de France, Lille, France (A.A.S., D.A., G.T.); Centre Hospitalier Régional Universitaire de Lille, Laboratory of Toxicology, Lille, France (A.A.S., D.A.); INSERM, Unité Mixte de Recherche S-850, Limoges, France (A.A.S., F.-L.S., P.M., N.P.); and CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France (F.-L.S., J.-m.G., P.M., N.P.)
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Abstract

Ethyl glucuronide (EtG) determination is increasingly used in clinical and forensic toxicology to document ethanol consumption. The enzymes involved in EtG production, as well as potential interactions with common drugs of abuse, have not been extensively studied. Activities of human liver (HLM), kidney (HKM), and intestinal (HIM) microsomes, as well as of 12 major human recombinant UDP-glucuronosyltransferases (UGTs), toward ethanol (50 and 500 mM) were evaluated in vitro using liquid chromatography-tandem mass spectrometry. Enzyme kinetic parameters were determined for pooled microsomes and recombinant UGTs with significant activity. Individual contributions of UGTs were estimated using the relative activity factor approach, proposed for scaling activities obtained with cDNA-expressed enzymes to HLM. Interaction of morphine, codeine, lorazepam, oxazepam, nicotine, cotinine, cannabinol, and cannabidiol (5, 10, 15 mg/l) with ethanol (1.15, 4.6, 11.5 g/l; i.e., 25, 100, 250 mM) glucuronidation was assessed using pooled HLM. Ethanol glucuronidation intrinsic clearance (Clint) was 4 and 12.7 times higher for HLM than for HKM and HIM, respectively. All recombinant UGTs, except UGT1A1, 1A6, and 1A10, produced EtG in detectable amounts. UGT1A9 and 2B7 were the most active enzymes, each accounting for 17 and 33% of HLM Clint, respectively. Only cannabinol and cannabidiol significantly affected ethanol glucuronidation. Cannabinol increased ethanol glucuronidation in a concentration-dependent manner, whereas cannabidiol significantly inhibited EtG formation in a noncompetitive manner (IC50 = 1.17 mg/l; inhibition constant (Ki) = 3.1 mg/l). UGT1A9 and 2B7 are the main enzymes involved in ethanol glucuronidation. In addition, our results suggest that cannabinol and cannabidiol could significantly alter ethanol glucuronidation.

Footnotes

  • A.A.S. is supported by a research grant from Damascus University, Syria.

  • dx.doi.org/10.1124/dmd.112.047878.

  • Received July 12, 2012.
  • Accepted December 10, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (3)
Drug Metabolism and Disposition
Vol. 41, Issue 3
1 Mar 2013
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Research ArticleArticles

Ethanol Glucuronidation: Enzymes and Potential Interactions

Alaa Al Saabi, Delphine Allorge, François-Ludovic Sauvage, Gilles Tournel, Jean-michel Gaulier, Pierre Marquet and Nicolas Picard
Drug Metabolism and Disposition March 1, 2013, 41 (3) 568-574; DOI: https://doi.org/10.1124/dmd.112.047878

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Research ArticleArticles

Ethanol Glucuronidation: Enzymes and Potential Interactions

Alaa Al Saabi, Delphine Allorge, François-Ludovic Sauvage, Gilles Tournel, Jean-michel Gaulier, Pierre Marquet and Nicolas Picard
Drug Metabolism and Disposition March 1, 2013, 41 (3) 568-574; DOI: https://doi.org/10.1124/dmd.112.047878
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