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15470160

Source:http://linkedlifedata.com/resource/pubmed/id/15470160

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pubmed-article:15470160pubmed:dateCreated2004-12-20lld:pubmed
pubmed-article:15470160pubmed:abstractTextTrans-3'-hydroxycotinine is a major metabolite of nicotine in humans and is mainly excreted as O-glucuronide in smoker's urine. Incubation of human liver microsomes with UDP-glucuronic acid produces not only trans-3'-hydroxycotinine O-glucuronide but also N-glucuronide. The formation of N-glucuronide exceeds the formation of O-glucuronide in most human liver microsomes, although N-glucuronide has never been detected in human urine. Trans-3'-hydroxycotinine N-glucuronidation in human liver microsomes was significantly correlated with nicotine and cotinine N-glucuronidations, which are catalyzed mainly by UDP-glucuronosyltransferase (UGT)1A4 and was inhibited by imipramine and nicotine, which are substrates of UGT1A4. Recombinant UGT1A4 exhibited substantial trans-3'-hydroxycotinine N-glucuronosyltransferase activity. These results suggest that trans-3'-hydroxycotinine N-glucuronidation in human liver microsomes would be mainly catalyzed by UGT1A4. In the present study, trans-3'-hydroxycotinine O-glucuronidation in human liver microsomes was thoroughly characterized, since trans-3'-hydroxycotinine O-glucuronide is one of the major metabolites of nicotine. The kinetics were fitted to the Michaelis-Menten equation with a K(m) of 10.0 +/- 0.8 mM and a V(max) of 85.8 +/- 3.8 pmol/min/mg. Among 11 recombinant human UGT isoforms expressed in baculovirus-infected insect cells, UGT2B7 exhibited the highest trans-3'-hydroxycotinine O-glucuronosyltransferase activity (1.1 pmol/min/mg) followed by UGT1A9 (0.3 pmol/min/mg), UGT2B15 (0.2 pmol/min/mg), and UGT2B4 (0.2 pmol/min/mg) at a substrate concentration of 1 mM. Trans-3'-hydroxycotinine O-glucuronosyltransferase activity by recombinant UGT2B7 increased with an increase in the substrate concentration up to 16 mM (10.5 pmol/min/mg). The kinetics by recombinant UGT1A9 were fitted to the Michaelis-Menten equation with K(m) = 1.6 +/- 0.1 mM and V(max) = 0.69 +/- 0.02 pmol/min/mg of protein. Trans-3'-hydroxycotinine O-glucuronosyltransferase activities in 13 human liver microsomes ranged from 2.4 to 12.6 pmol/min/mg and were significantly correlated with valproic acid glucuronidation (r = 0.716, p < 0.01), which is catalyzed by UGT2B7, UGT1A6, and UGT1A9. Trans-3'-hydroxycotinine O-glucuronosyltransferase activity in human liver microsomes was inhibited by imipramine (a substrate of UGT1A4, IC(50) = 55 microM), androstanediol (a substrate of UGT2B15, IC(50) = 169 microM), and propofol (a substrate of UGT1A9, IC(50) = 296 microM). Interestingly, imipramine (IC(50) = 45 microM), androstanediol (IC(50) = 21 microM), and propofol (IC(50) = 41 microM) also inhibited trans-3'-hydroxycotinine O-glucuronosyltransferase activity by recombinant UGT2B7. These findings suggested that trans-3'-hydroxycotinine O-glucuronidation in human liver microsomes is catalyzed by mainly UGT2B7 and, to a minor extent, by UGT1A9.lld:pubmed
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pubmed-article:15470160pubmed:authorpubmed-author:NakajimaMikiMlld:pubmed
pubmed-article:15470160pubmed:authorpubmed-author:YokoiTsuyoshi...lld:pubmed
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pubmed-article:15470160pubmed:authorpubmed-author:TamuraOsamuOlld:pubmed
pubmed-article:15470160pubmed:authorpubmed-author:IshibashiHiro...lld:pubmed
pubmed-article:15470160pubmed:authorpubmed-author:KatohMikiMlld:pubmed
pubmed-article:15470160pubmed:authorpubmed-author:KanohAyanoAlld:pubmed
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pubmed-article:15470160pubmed:pagination23-30lld:pubmed
pubmed-article:15470160pubmed:dateRevised2006-11-15lld:pubmed
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pubmed-article:15470160pubmed:year2005lld:pubmed
pubmed-article:15470160pubmed:articleTitleTrans-3'-hydroxycotinine O- and N-glucuronidations in human liver microsomes.lld:pubmed
pubmed-article:15470160pubmed:affiliationDrug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.lld:pubmed
pubmed-article:15470160pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:15470160pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed
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