Journal article
Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms
The Journal of pharmacology and experimental therapeutics, Vol.299(3), pp.998-1006
12/2001
Handle:
https://hdl.handle.net/2376/106360
PMID: 11714888
Abstract
Interindividual variability in acetaminophen (APAP) glucuronidation may contribute to differences in susceptibility to APAP intoxication in humans. The purpose of this study was to identify the relevant UDP-glucuronosyltransferase (UGT) isoforms mediating APAP-UGT activity in human liver microsomes (HLMs). APAP-UGT activities and enzyme kinetics were determined using HLMs from 56 donors and nine recombinant human UGTs. Activities mediated by UGT1A1, UGT1A4, UGT1A9, and UGT2B7, and relative UGT1A6 protein content were quantified using 20 livers. More than 15-fold variation in liver microsomal APAP-UGT activities was observed with a distribution skewed toward lower activities. Although most UGTs could glucuronidate APAP, UGT1A1, UGT1A6, and UGT1A9 were most active. UGT1A6 was a relatively high-affinity (K(m) = 2.2 mM), low-capacity enzyme; UGT1A1 was intermediate in affinity (K(m) = 9.4 mM) and capacity; and UGT1A9 was a low-affinity (K(m) = 21 mM), high-capacity enzyme. K(m) values were similar to UGT1A1 in high- and intermediate-activity HLMs (6-10 mM) and UGT1A9 in low-activity HLMs (10-55 mM). APAP-UGT activities correlated best with propofol-UGT (r = 0.85; UGT1A9) and bilirubin-UGT (r = 0.66; UGT1A1) activities, but poorly with UGT1A6 protein (r = 0.30). A kinetic model was constructed from these data that identified UGT1A9 as the predominant APAP-UGT (>55% total activity) in HLMs over a clinically relevant APAP concentration range (50 microM-5 mM). UGT1A1 was also predicted to contribute substantially at toxic concentrations (>1 mM; >28% activity), whereas UGT1A6 was most active at relatively low concentrations (<50 microM; >29% activity).
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Details
- Title
- Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms
- Creators
- M H Court - Molecular Pharmacogenetics, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. michael.court@tufts.eduS X DuanL L von MoltkeD J GreenblattC J PattenJ O MinersP I Mackenzie
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.299(3), pp.998-1006
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- United States
- Grant note
- DK-58496 / NIDDK NIH HHS RR-00104 / NCRR NIH HHS GM-61834 / NIGMS NIH HHS DA-05258 / NIDA NIH HHS RR-00054 / NCRR NIH HHS DA-13209 / NIDA NIH HHS MH-58435 / NIMH NIH HHS
- Identifiers
- 99900546810201842
- Language
- English
- Resource Type
- Journal article