Abstract：
:Nicotine biotransformation affects the smoking habits of addicted individuals and therefore their health risk. Using an improved analytical method, we have discovered that the human UDP-glucuronosyltransferase (UGT) 2B10, a liver enzyme previously unknown to conjugate nicotine or exhibit considerable activity toward any compound, plays a major role in nicotine inactivation by direct conjugation with glucuronic acid at the aromatic nitrogen atom. The K(m) value of recombinant UGT2B10 for nicotine (0.29 mM) was similar to that determined for human liver microsomes (0.33 mM), whereas the K(m) value of UGT1A4 for nicotine was almost 10-fold greater (2.4 mM). UGT2B10 was also more active than UGT1A4 in N-glucuronidation of cotinine (oxidative nicotine metabolite), whereas UGT2B7 exhibited only low nicotine glucuronidation activity and was essentially inactive toward cotinine. UGT1A9 did not glucuronidate nicotine or cotinine. Quantitative reverse transcription-polymerase chain reaction showed that UGT2B10 mRNA was exclusively expressed in human liver, whereas UGTs 1A4 and 2B7 were expressed at comparable, although somewhat lower, levels in liver and several other extrahepatic tissues, including kidney and intestine. These findings for UGT2B10 (but not for UGT1A4 and UGT2B7) were mirrored by human tissue activities because nicotine and cotinine glucuronidation rates in intestine microsomes were less than 0.1% that of human liver microsomes. These novel findings solve two seemingly separate questions: which UGT is primarily responsible for nicotine glucuronidation in human liver, and what conjugation reactions are catalyzed by UGT2B10.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Kaivosaari S,Toivonen P,Hesse LM,Koskinen M,Court MH,Finel Mdoi
10.1124/mol.107.037093subject
Has Abstractpub_date
2007-09-01 00:00:00pages
761-8issue
3eissn
0026-895Xissn
1521-0111pii
mol.107.037093journal_volume
72pub_type
杂志文章abstract：:Thiourea, phenylthiourea, and methimazole perfused into rat liver stimulated the biliary efflux of GSSG without affecting the excretion of GSH into either the bile or the caval perfusate. The thiocarbamide moiety appears essential, since perfusion with urea, phenylurea, or N-methylimidazole did not stimulate GSSG rele...
journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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更新日期：1999-05-01 00:00:00
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journal_title：Molecular pharmacology
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更新日期：1991-03-01 00:00:00
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doi：
更新日期：1988-09-01 00:00:00
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journal_title：Molecular pharmacology
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更新日期：2006-07-01 00:00:00
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journal_title：Molecular pharmacology
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更新日期：1995-08-01 00:00:00
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journal_title：Molecular pharmacology
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doi：
更新日期：1990-05-01 00:00:00
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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更新日期：1991-08-01 00:00:00
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journal_title：Molecular pharmacology
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更新日期：1992-04-01 00:00:00
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