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.

Lhoëst, G J;Otte, Jean-Bernard;de Jong, A P;Meiring, H D;Latinne, Dominique;et.al.
(1998) Journal of Mass Spectrometry — Vol. 33, n° 10, p. 936-942 (1998)

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  • Lhoëst, G J
    Author
  • Otte, Jean-Bernard
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  • de Jong, A P
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  • Meiring, H D
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  • Maton, NicoleUCLouvain
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  • Latinne, DominiqueUCLouvain
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Abstract
The isolation from human liver microsomes and identification 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-IMM-125-CH2OH main metabolite and cyclophilin A-IMM-125 complexes. However, when formed, the IMM-125-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 CO2 and of m/z 1749 by loss of CO2 and H2O or glycerol. Since immunosuppressive 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.
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Lhoëst, G. J., Otte, J.-B., de Jong, A. P., Meiring, H. D., Verbeeck, R. K., Zurini, M., Maton, N., & Latinne, D. (1998). 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. Journal of Mass Spectrometry, 33(10), 936-942. https://doi.org/10.1002/(SICI)1096-9888(1998100)33:10<936::AID-JMS702>3.0.CO;2-6 (Original work published 1998)