DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on October 28, 2005; DOI: 10.1124/dmd.105.005652

0090-9556/06/3402-199-202$20.00
DMD 34:199-202, 2006

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.105.005652v1
34/2/199    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kuehl, G. E.
Right arrow Articles by Lampe, J. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kuehl, G. E.
Right arrow Articles by Lampe, J. W.
SHORT COMMUNICATION

GLUCURONIDATION OF THE ASPIRIN METABOLITE SALICYLIC ACID BY EXPRESSED UDP-GLUCURONOSYLTRANSFERASES AND HUMAN LIVER MICROSOMES

Gwendolyn E. Kuehl, Jeannette Bigler, John D. Potter, and Johanna W. Lampe

Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington

Acetylsalicylic acid (aspirin) is a common nonsteroidal anti-inflammatory drug used for treatment of pain and arthritis. In the body, acetylsalicylic acid is rapidly deacetylated to form salicylic acid. Both compounds have been proposed as anti-inflammatory agents. Major metabolites of salicylic acid are its acyl and phenolic glucuronide conjugates. Formation of these conjugates, catalyzed by UDP-glucuronosyltransferases (UGTs), decreases the amount of pharmacologically active salicylic acid present. We aimed to identify the UGTs catalyzing the glucuronidation of salicylic acid using both heterologously expressed enzymes and pooled human liver microsomes (HLMs) and to develop a liquid chromatographytandem mass spectrometry method to quantify glucuronidation activity of UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17 Supersomes. All UGTs tested, except 1A4, 2B15, and 2B17, catalyzed salicylic acid phenolic and acyl glucuronidation. Ratios of salicylic acid phenolic to acyl glucuronide formation varied more than 12-fold from 0.5 for UGT1A6 to 6.1 for UGT1A1. These results suggest that all UGTs except 1A4, 2B15, and 2B17 might be involved in the glucuronidation of salicylic acid in vivo. From comparisons of apparent Km values determined in pooled HLMs and in expressed UGTs, UGT2B7 was suggested as a likely catalyst of salicylic acid acyl glucuronidation, whereas multiple UGTs were suggested as catalysts of phenolic glucuronidation. The results of this UGT screening may help target future evaluation of the effects of UGT polymorphisms on response to aspirin in clinical and population-based studies.

Address correspondence to: Johanna W. Lampe, 1100 Fairview Ave. N. M4-B402, P.O. Box 19024, Seattle, WA. 98109. E-mail: jlampe{at}fhcrc.org Address correspondence to: Johanna Lampe, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 100 Fairview Ave N, M4-B402, PO Box 19024, Seattle, WA 98109. Email: jlampe{at}fhcrc.org




This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
S. T. Stern, M. N. Tallman, K. K. Miles, J. K. Ritter, and P. C. Smith
Androgen Regulation of Renal Uridine Diphosphoglucuronosyltransferase 1A1 in Rats
Drug Metab. Dispos., September 1, 2008; 36(9): 1737 - 1739.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
E. K. Chow, A. Castrillo, A. Shahangian, L. Pei, R. M. O'Connell, R. L. Modlin, P. Tontonoz, and G. Cheng
A role for IRF3-dependent RXR{alpha} repression in hepatotoxicity associated with viral infections
J. Exp. Med., November 27, 2006; 203(12): 2589 - 2602.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.