Identification of the Molecular Mechanisms underlying the Gastrointestinal Toxicity of the Immunosuppressants Mycophenolate Mofetil and Enteric-coated Mycophenolate Sodium using a Proteo-Metabolomic Approach

Abstract

Mycophenolic acid (MPA) is the cornerstone of most immunosuppressive drug regimens after organ transplantation. However, gastrointestinal side effects diminish MPA's otherwise outstanding safety and efficiency. Using a unique cell culture model featuring the human colon cancer cell line LS180 and a combination of molecular biology methods and a non-targeted proteo-metabolomic strategy based on high-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy, we were able to identify impairment of LS180 cell lipid metabolism as well as effects on structural proteins and nucleotide-dependent processes as main mediators of the negative effects of MPA on gastrointestinal barrier function.