Abstract
Acyl-adenylates and acyl-CoA thioesters of bile acids (BAs) are reactive acyl-linked metabolites that have been shown to undergo transacylation-type reactions with the thiol group of glutathione (GSH), leading to the formation of thioester-linked GSH conjugates. In the current study, we examined the transformation of cholyl-adenylate (CA–AMP) and cholyl-coenzyme A thioester (CA–CoA) into a cholyl- S-acyl GSH (CA–GSH) conjugate by rat hepatic glutathione S-transferase (GST). The reaction product was analyzed by liquid chromatography (LC)/electrospray ionization (ESI)–linear ion trap mass spectrometry (MS). The GST-catalyzed formation of CA–GSH occurred with both CA–AMP and CA–CoA. Ursodeoxycholic acid, lithocholic acid, and 2,2,4,4- 2H 4-labeled lithocholic acid were administered orally to biliary fistula rats, and their corresponding GSH conjugates were identified in bile by LC/ESI–MS 2. These in vitro and in vivo studies confirm a new mode of BA conjugation in which BAs are transformed into their GSH conjugates via their acyl-linked intermediary metabolites by the catalytic action of GST in the liver, and the GSH conjugates are then excreted into the bile.
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