ABSTRACT
Nonsteroidal anti-inflammatory drugs (NSAIDs) containing carboxylic acid are conjugated with coenzyme A (CoA) or glucuronic acid in the body. It has been suggested that these conjugates are associated with toxicities, such as liver injury and anaphylaxis, through their binding via trans-acylation to cellular proteins. Although studies on glucuronidation have progressed, studies on CoA conjugation of drugs catalyzed by acyl-CoA synthetase (ACS) enzymes are still in the early stages. This study aimed to clarify the human ACS isoforms responsible for CoA-conjugation of NSAIDs through consideration of the hepatic expression levels of ACS isoforms. We found that among 10 types of NSAIDs, propionic acid-class NSAIDs, namely, alminoprofen, flurbiprofen, ibuprofen, ketoprofen, and loxoprofen, were conjugated with CoA in the human liver, whereas NSAIDs in the other classes, including diclofenac and mefenamic acid, were not. qRT-PCR revealed that among the 26 ACS isoforms, ACSL1 was the most highly expressed in the human liver, followed by ACSM2B. The propionic acid-class NSAIDs were conjugated with CoA by recombinant human ACSL1. The protein binding abilities of the CoA conjugates and the glucuronide forms of propionic acid-class NSAIDs were compared as an index of toxicity. The CoA conjugates had stronger adduct formation with liver microsomal proteins than glucuronides for all 5 propionic acid-class NSAIDs. In conclusion, we found that propionic acid-class NSAIDs could be conjugated to CoA by ACSL1 in the human liver to form CoA conjugates, which likely cause toxicity by protein adduct formation.
