Received for publication May 26, 2005.
Revised October 26, 2005.
Accepted for publication October 26, 2005.

Glucuronidation of the aspirin metabolite salicylic acid by expressed UGTs and human liver microsomes

Abstract

Acetylsalicylic acid (aspirin) is a common nonsteroidal anti-inflammatory drug (NSAID) 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 (HLM) and to develop a liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method to quantify glucuronidation activity of UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15 and 2B17 Supersomes^TM. 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 K_m values determined in pooled HLM and in expressed UGTs, UGT2B7 was suggested as a likely catalyst of salicylic acid acyl glucuronidation while multiple UGTs were suggested as catalysts of phenolic glucuronidation. The results of this UGT screening may help target future evaluation of effects of UGT polymorphisms on response to aspirin in clinical and population-based studies.

Key words: glucuronidation, non-steroidal anti-inflammatory drugs, UDP glucuronyltransferases

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