Formation of glycine conjugate and (-)-(R)-enantiomer from (+)-(S)-2-phenylpropionic acid suggesting the formation of the CoA thioester intermediate of (+)-(S)-enantiomer in dogs

• Published in: Chirality (New York, N.Y.) Vol. 4; no. 6; p. 342
• Main Authors: Tanaka, Y, Shimomura, Y, Hirota, T, Nozaki, A, Ebata, M, Takasaki, W, Shigehara, E, Hayashi, R, Caldwell, J
• Format: Journal Article
• Language: English
• Published: United States 1992
• Subjects: Animals; Chromatography, High Pressure Liquid; Coenzyme A - metabolism; Dogs; Glucuronates - metabolism; Glucuronic Acid; Glycine - blood; Glycine - metabolism; Glycine - urine; Liver - cytology; Liver - metabolism; Male; Molecular Conformation; Phenylpropionates - blood; Phenylpropionates - metabolism; Phenylpropionates - urine; Stereoisomerism
• ISSN: 0899-0042
• DOI: 10.1002/chir.530040603

It has been proposed that the chiral inversion of the 2-arylpropionic acids is due to the stereospecific formation of the (-)-R-profenyl-CoA thioesters which are putative intermediates in the inversion. Accordingly, amino acid conjugation, for which the CoA thioesters are obligate intermediates, should be restricted to those optical forms which give rise to the (-)-R-profenyl-CoA, i.e., the racemates and the (-)-(R)-isomers. We have examined this problem in dogs with respect to 2-phenylpropionic acid(2-PPA). Regardless of the optical configuration of 2-phenylpropionic acid administered, the glycine conjugate was the major urinary metabolite and this was shown to be exclusively the (+)-(S)-enantiomer by chiral HPLC. Both (-)-(R)- and (+)-(S)-2-phenylpropionic acid were present in plasma after the administration of either antipode, and further evidence of the chiral inversion of both enantiomers was provided by the presence of some 25% of the opposite enantiomer in the free 2-phenylpropionic acid and its glucuronide excreted in urine after administration of (-)-(R)- and (+)-(S)-2-phenylpropionic acid. The (+)-(S)-enantiomer underwent chiral inversion to the (-)-(R)-antipode when incubated with dog hepatocytes. These data suggests that both enantiomers of 2-phenylpropionic acid are substrates for canine hepatic acyl CoA ligase(s) and thus undergo chiral inversion, but that the CoA thioester of only (+)-(S)-2-phenylpropionic acid is a substrate for the glycine N-acyl transferase. These studies are presently being extended to the structure and species specificity of the reverse inversion and amino acid conjugation of profen NSAIDs.