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

J Mass Spectrom. 1998 Oct;33(10):936-42. doi: 10.1002/(SICI)1096-9888(1998100)33:10<936::AID-JMS702>3.0.CO;2-6.

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.

MeSH terms

  • Biotransformation
  • Chromatography, High Pressure Liquid
  • Cyclosporins / chemistry*
  • Cyclosporins / pharmacokinetics
  • Cyclosporins / pharmacology
  • Humans
  • Immunosuppressive Agents / chemistry*
  • Immunosuppressive Agents / isolation & purification
  • Immunosuppressive Agents / pharmacology
  • In Vitro Techniques
  • Indicators and Reagents
  • Liver / chemistry
  • Mass Spectrometry
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism*
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Peptidylprolyl Isomerase / chemistry*

Substances

  • Cyclosporins
  • IMM 125
  • Immunosuppressive Agents
  • Indicators and Reagents
  • Peptidylprolyl Isomerase