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First published on June 18, 2007; DOI: 10.1124/mol.107.037093

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Received for publication April 13, 2007.
Revised June 18, 2007.
Accepted for publication June 18, 2007.

Nicotine glucuronidation and the human UDP-glucuronosyltransferase UGT2B10

Sanna Kaivosaari 1, Paivi Toivonen 1, Leah M. Hesse 2, Mikko Koskinen 3, Michael H. Court 2, Moshe Finel 4*

1 Orion Parma and University of Helsinki 2 Department of Pharmacology and Experimental Therapeutics, Tufts University, Boston 3 Department of Pharmacokinetics and Bioanalytics, Orion Parma, P.O. Box 65, 02101, Finland 4 University of Helsinki

* Address correspondence to: E-mail: moshe.finel{at}helsinki.fi

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 towards any compound, plays a major role in nicotine inactivation by direct conjugation with glucuronic acid at the aromatic nitrogen atom. The Km of recombinant UGT2B10 for nicotine (0.29 mM) was similar to that determined for human liver microsomes (0.33 mM), whereas the Km of UGT1A4 for nicotine was almost 10-fold higher (2.4 mM). UGT2B10 was also more active than UGT1A4 in N-glucuronidation of cotinine (oxidative nicotine metabolite), while UGT2B7 exhibited only low nicotine glucuronidation activity and was essentially inactive towards cotinine. UGT1A9 did not glucuronidate nicotine or cotinine. Quantitative RT-PCR showed that UGT2B10 mRNA was exclusively expressed in human liver, while 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 since 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, namely which is the UGT that is primarily responsible for nicotine glucuronidation in human liver, and what conjugation reactions are catalyzed by UGT2B10.


Key words: Mass Spectroscopy, Enzymology, Structure/function/mechanism, UDP-glucuronyltransferases


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