Stereoselective arylpropionyl-CoA thioester formation in vitro

Area of Science:

• Pharmacology
• Biochemistry
• Drug Metabolism

Background:

• Enantiomeric inversion of certain arylpropionic acids (e.g., fenoprofen, ibuprofen) has significant toxicological and therapeutic implications.
• Understanding the mechanisms of this inversion is crucial for predicting drug behavior and optimizing therapeutic outcomes.

Purpose of the Study:

• To investigate the role of arylpropionyl-CoA thioester formation in the enantiomeric inversion of fenoprofen, ibuprofen, and flurbiprofen.
• To identify the specific tissues and subcellular fractions involved in thioester formation and subsequent inversion.

Main Methods:

• Incubation of rat tissue homogenates and subcellular fractions with enantiomers of fenoprofen, ibuprofen, and flurbiprofen.
• Analysis of arylpropionyl-CoA thioester formation and racemization/inversion kinetics.
• Comparison of thioester formation across various rat tissues and subcellular compartments.

Main Results:

• Stereoselective formation of CoA thioesters was observed for (R)-fenoprofen and (R)-ibuprofen, correlating with in vivo inversion.
• Thioester formation occurred primarily in liver mitochondria and microsomes.
• Liver homogenates demonstrated the highest efficiency (at least 50-fold) for thioester formation, indicating its major role in inversion.

Conclusions:

• The R- to S-enantiomeric inversion of arylpropionic acids likely proceeds through stereoselective CoA thioester formation.
• Enzymatic racemization and hydrolysis of these thioesters regenerate the free acid, with liver being a primary site for this metabolic pathway.