Identification of human UDP-glucuronosyltransferase responsible for the glucuronidation of niflumic acid in human liver.

Abstract:

PURPOSE:To assess the uridine diphosphate (UDP)-glucuronosyltransferase (UGT) isozymes involved in the glucuronidation of niflumic acid in human liver. METHODS:The glucuronidation activity of niflumic acid was determined in liver microsomes and recombinant UGT isozymes by incubation of niflumic acid with UDP-glucuronic acid (UDPGA). RESULTS:Incubation of niflumic acid with liver microsomes and UDPGA produced one peak, which was identified as a glucuronide from mass spectrometric analysis. A study involving a panel of recombinant human UGT isozymes showed that glucuronidation activity was highest in UGT1A1 among the isozymes investigated. The glucuronidation in human liver microsomes (HLMs) followed Michaelis-Menten kinetics with a Km value of 16 microM, which is similar to that found with recombinant UGT1A1. The glucuronidation activity of niflumic acid in microsomes from eight human livers significantly correlated with UGT1A1-catalyzed estradiol 3beta-glucuronidation activity (r=0.78, p<0.05). Beta-estradiol inhibited niflumic acid glucuronidation with an IC50 of 25 microM in HLMs, comparable to that for UGT1A1. CONCLUSIONS:These findings indicate that UGT1A1 is the main isozyme involved in the glucuronidation of niflumic acid in the human liver.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Mano Y,Usui T,Kamimura H

doi

10.1007/s11095-006-0250-5

subject

Has Abstract

pub_date

2006-07-01 00:00:00

pages

1502-8

issue

7

eissn

0724-8741

issn

1573-904X

journal_volume

23

pub_type

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