Isolation, identification and immunosuppressive activity of a new IMM-125 metabolite from human liver microsomes. identification of its cyclophilin A-IMM-125 metabolite complex by nanospray tandem mass spectrometry

✍ Scribed by Lhoëst, G. J. J.; de Jong, A. P. J. M.; Meiring, H. D.; Maton, N.; Latinne, D.; Verbeeck, R. K.; Otte, J. B.; Zurini, M.

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 296 KB
• Volume: 33
• Category: Article
• ISSN: 1076-5174
• DOI: 10.1002/(sici)1096-9888(1998100)33:10<936::aid-jms702>3.0.co;2-6

✦ Synopsis

The isolation from human liver microsomes and identiÐcation by electrospray mass spectrometry and tandem mass spectrometry of a new metabolite of IMM-125 resulting from the biotransformation of the amino acid 1 vinylic methyl group to a carboxylic acid, called the IMM-125-COOH metabolite, is described. It was found that the complex of this new metabolite with cyclophilin A is formed less easily than the corresponding cyclophilin A-IMMmain metabolite and cyclophilin A-IMM-125 complexes. However, when formed, the IMM-125-125-CH 2 OH COOH metabolite-cyclophilin A complex requires more collision-induced dissociation (CID) to dissociate the complex than the complexes formed with the two other ligands. The nanospray tandem mass spectrum of the IMM-125-COOH metabolite-cyclophilin A complex (m/z 1755) gives rise to cyclophilin A-ligand complexes of m/z 1751 by elimination of and of m/z 1749 by loss of and or glycerol. Since immunosuppressive CO 2 CO 2 H 2 O activity is known to be dependent on the formation of a binary complex between cyclophilin A and the drug and since the target for the binary complex was found to be the calcium-and calmodulin-dependent protein phosphatase, calcineurin, it could be interesting to measure for structurally related immunosuppressive drugs the CID energy necessary to dissociate the binary complexes in order to evaluate whether a correlation with the phosphatase activity could be derived.