Identification of the human liver UDP-glucuronosyltransferase involved in the metabolism of p-ethoxyphenylurea (dulcin) |
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Authors: | Yoshihiro Uesawa Adam G Staines David Lockley Kiminori Mohri Brian Burchell |
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Institution: | (1) Department of Pharmaceutics, Clinical Pharmaceutics Laboratory, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan;(2) Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK |
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Abstract: | Dulcin (DL), now banned, was once a widely used artificial sweetener. DL possesses an ureido group that is metabolized by
direct glucuronidation in rabbit liver microsomes. Dulcin N-glucuronide (DNG) is the only type of ureido N-glucuronide known to date; ureido glucuronidation in humans has not been previously reported. Accordingly, the glucuronidation
of DL was studied using human liver microsomes (HLM) and expressed human UDP-glucuronosyltransferase (UGT) enzymes. The average
K
m and V
max values from nine HLM samples were 2.10 mM and 0.156 nmol/mg/min, respectively. Of the six human UGT isoforms screened for
their ability to glucuronidate DL, only UGT1A1 and UGT1A9 showed activity. The apparent K
m values using UGT1A1 and UGT1A9 were 5.06 and 6.99 mM, and the apparent V
max values were 0.0461 and 0.106 nmol/min/mg, respectively. Phenolphthalein, a substrate for UGT1A9, inhibited DL glucuronidation
in HLM competitively (K
i = 0.356 mM), but bilirubin, a substrate for UGT1A1, did not. These results suggest that UGT1A9 is a key enzyme catalyzing
the glucuronidation of DL. |
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Keywords: | Dulcin UGT1A1 UGT1A9 Ureido group Glucuronidation |
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