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

Abstract : Background: Ethylglucuronide (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. Methods: Activities of human liver (HLM), kidney (HKM) and intestinal (HIM) microsomes, as well as of twelve 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 (RAF) 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. Results: Ethanol glucuronidation intrinsic clearance (Cl(int)) 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 Cl(int), 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 non-competitive manner (IC(50)=1.17 mg/L; Ki=3.1 mg/L). Conclusions: UGT1A9 and 2B7 are the main enzymes involved in ethanol glucuronidation. In addition, our results suggest that cannabinol and cannabidiol could alter significantly ethanol glucuronidation.
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Submitted on : Wednesday, December 19, 2012 - 10:06:47 AM
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Alaa Al Saabi, Delphine Allorge, François-Ludovic Sauvage, Gilles Tournel, Jean-Michel Gaulier, et al.. Involvement of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 in Ethanol Glucuronidation, and Interactions with Common Drugs of Abuse.. Drug Metabolism and Disposition, American Society for Pharmacology and Experimental Therapeutics (ASPET), 2012, epub ahead of print. ⟨10.1124/dmd.112.047878⟩. ⟨inserm-00766822⟩



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