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Drug Metabolism and Disposition Fast Forward
First published on February 2, 2005; DOI: 10.1124/dmd.104.002139

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Received for publication September 1, 2004.
Revised January 28, 2005.
Accepted for publication January 28, 2005.

Biosynthesis of Dobutamine Monoglucuronides and Glucuronidation of Dobutamine by Recombinant Human UDP-glucuronosyltransferases

Anna Alonen 1, Olli Aitio 1, Kati Hakala 1, Leena Luukkanen 1, Moshe Finel 1, Risto Kostiainen 2*

1 University of Helsinki 2 Viikki Drug Discovery Technology Center (DDTC)

* Address correspondence to: E-mail: risto.kostiainen{at}helsinki.fi

Abstract

Selected aspects of dobutamine glucuronidation were studied in detail. There are potentially four sites at which dobutamine can be conjugated to glucuronic acid. Three of the four dobutamine monoglucuronides that can be formed were enzymatically synthesized using pig liver microsomes, isolated, and characterized by tandem mass spectrometry, and 1H and 13C NMR spectroscopy. Analysis of dobutamine glucuronidation by liver microsomes from various sources revealed large variability in the ratios of the three regioisomers. Interestingly, catecholic dobutamine meta O-glucuronide, by far the major product synthesized with human liver microsomes, was only a minor product for rat liver microsomes. Rabbit liver microsomes yielded diglucuronides, in addition to monoglucuronides. Activities of individual recombinant human UDP-glucuronosyltransferases (UGTs) were investigated, and the results suggested that dobutamine glucuronidation in the human liver is mainly carried out by UGTs 2B7 and 1A9. Among the extrahepatic UGTs, the formation of monoglucuronides, mainly catecholic meta O-glucuronide, by UGTs 1A7 and 1A8 was similar to that by 1A9, whereas UGT1A10 also efficiently catalyzed the formation of catecholic dobutamine para O-glucuronide.


Key words: glucuronidation, liver microsomes, structure elucidation, UDP glucuronyltransferases


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T. Sten, S. Qvisen, P. Uutela, L. Luukkanen, R. Kostiainen, and M. Finel
Prominent but Reverse Stereoselectivity in Propranolol Glucuronidation by Human UDP-Glucuronosyltransferases 1A9 and 1A10
Drug Metab. Dispos., September 1, 2006; 34(9): 1488 - 1494.
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