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First published on January 10, 2008; DOI: 10.1124/dmd.107.019281

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Received for publication October 22, 2007.
Revised January 7, 2008.
Accepted for publication January 9, 2008.

Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine 6-glucuronidation and its kinetic properties

Shuji Ohno 1, Kiyoshi Kawana 1, Shizuo Nakajin 2*

1 Hoshi University School of Pharmacy and Pharmaceutical Sciences 2 Hoshi University School of pharmacy and Pharmaceitical Sciences

* Address correspondence to: E-mail: nakajin{at}hoshi.ac.jp

Abstract

The metabolic conversion of morphine to morphine 6-glucuronide (M6G) seems to play a significant role in mediation of the clinical effect of morphine because of the superior analgesic effect of M6G. Therefore, it would be of great interest to clarify the specificity of morphine 6-glucuronidation by UGT isozymes. We investigated the specificity of morphine 6-glucuronidation catalyzed by recombinant human UGT isozymes in microsomes from baculovirus-infected insect cells. The morphine glucuronidation activity of recombinant human UGT isozymes incubated with morphine and UDP-glucuronic acid was determined by HPLC with a fluorescence detector. Not only UGT2B7, which is well known to catalyze morphine 6-glucuronidation, but also UGT1A1 and UGT1A8 effectively catalyzed morphine 6-glucuronidation at relatively low morphine concentrations (<100 µM). The kinetics of both isozymes at the low substrate concentrations showed hyperbolic Michaelis-Menten kinetics. However, as the morphine concentration approached 100 µM, morphine 6-glucuronidation activity gradually decreased and the kinetics closely resembled substrate inhibition Michaelis-Menten kinetic behavior. The Km values were 67.9 µM and 68.1 µM and the Ksi values were 218.9 µM and 88.0 µM for UGT1A1 and 1A8, respectively. These kinetics are basically different from that of morphine 6-glucuronidation by UGT2B7, which suggested biphasic Michaelis-Menten kinetic behavior. Furthermore, to estimate the contribution of these UGT isozymes in M6G formation in vivo, the expression levels of UGT1A1 and 1A8 mRNA in human liver and intestine were determined by reverse transcription real-time PCR. The results strongly suggest that UGT1A1 and UGT1A8 are isozymes involved in morphine 6-glucuronidation in vivo, as is UGT2B7 in humans.


Key words: drug disposition, pharmacokinetics, UDP glucuronyltransferases


This article has been cited by other articles:


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A. E. Schwaninger, M. R. Meyer, J. Zapp, and H. H. Maurer
The Role of Human UDP-Glucuronyltransferases on the Formation of the Methylenedioxymethamphetamine (Ecstasy) Phase II Metabolites R- and S-3-Methoxymethamphetamine 4-O-Glucuronides
Drug Metab. Dispos., November 1, 2009; 37(11): 2212 - 2220.
[Abstract] [Full Text] [PDF]


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