1: J Mass Spectrom 1998 Oct;33(10):936-42
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.
Lhoest GJ, de Jong AP, Meiring HD, Maton N, Latinne D, Verbeeck RK, Otte
JB, Zurini M
Department of Pharmaceutical Sciences-UCL Pharmacokinetics and Metabolism
Unit-FATC Laboratory of Mass Spectrometry, Brussels, Belgium.
lhoest@fatc.ucl.ac.be
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.
PMID: 9821326, UI: 99038767