Uridine diphosphate sugar-selective conjugation of an aldose reductase inhibitor (AS-3201) by UDP-glucuronosyltransferase 2B subfamily in human liver microsomes

N-Glucosidation is known as a major metabolic reaction for barbiturates in humans. However, the enzyme(s) involved in this N-glucosidation has not been clarified yet. Thus, to clarify the enzyme(s) involved in the N-glucosidation in human liver microsomes, we investigated the N-glucosyltransferase a...

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Bibliographic Details
Published in:Biochemical pharmacology 2004-04, Vol.67 (7), p.1269-1278
Main Authors: Toide, Kenji, Terauchi, Yoshiaki, Fujii, Toshihiko, Yamazaki, Hiroshi, Kamataki, Tetsuya
Format: Article
Language:English
Subjects:
Aldehyde Reductase - antagonists & inhibitors
Aldose reductase inhibitor
Biological and medical sciences
Glucosidation
Glucuronosyltransferase - metabolism
Humans
Isoenzymes - metabolism
Medical sciences
Microsomes, Liver - enzymology
Microsomes, Liver - metabolism
Pharmacology. Drug treatments
Pyrazines - pharmacology
Recombinant Proteins - metabolism
Relative activity factor
Spiro Compounds - pharmacology
UDP-glucose
UDP-glucuronosyltransferase
Uridine Diphosphate Glucose - metabolism
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Summary:N-Glucosidation is known as a major metabolic reaction for barbiturates in humans. However, the enzyme(s) involved in this N-glucosidation has not been clarified yet. Thus, to clarify the enzyme(s) involved in the N-glucosidation in human liver microsomes, we investigated the N-glucosyltransferase activity in recombinant UDP-glucuronosyltransferases (UGTs) using AS-3201, an aldose reductase inhibitor, as a substrate. AS-3201 was found to be biotransformed to both N-glucoside and N-glucuronide in human liver microsomes. The N-glucosyltransferase activities were detectable with multiple UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT2B4, UGT2B7, and UGT2B15). In contrast, the N-glucuronyltransferase activities for the same substrate were seen with UGT1A (UGT1A1, UGT1A3, UGT1A4, and UGT1A9) but not UGT2B isoforms. We then determined the relative activity factor of each recombinant UGT and estimated the contribution of each UGT isoform to the N-glucosidation in human liver microsomes. The results showed that UGT2B isoforms mainly contribute to AS-3201 N-glucosidation in human liver microsomes. In addition, the activity of AS-3201 N-glucosyltransferase significantly correlated with that of amobarbital N-glucosyltransferase in microsomes from sixteen human livers ( r=0.964, P
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2003.11.010