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The acyl glucuronide metabolite of mycophenolic acid induces tubulin polymerization in vitro

Authors
Journal
Clinical Biochemistry
0009-9120
Publisher
Elsevier
Publication Date
Volume
43
Identifiers
DOI: 10.1016/j.clinbiochem.2009.08.023
Keywords
  • Mycophenolic Acid
  • Immunosuppression
  • Acyl Glucuronide
  • Tubulin Polymerization
  • Antiproliferative Effect
Disciplines
  • Biology

Abstract

Abstract Objectives The acyl glucuronide (AcMPAG) of mycophenolic acid (MPA) forms covalent protein adducts and possesses antiproliferative properties independent of IMPDH inhibition. The underlying mechanism is unknown. Disorganized tubulin polymerization prevents cell cycle progression. We investigated whether AcMPAG interacts with tubulin polymerization. Design and methods AcMPAG (1.0–100 μM) was incubated with bovine tubulin in the presence of GTP. Polymerization was followed at 340 nm. The time until onset and the extent of polymerization were determined. MPA (100 μM), phenolic glucuronide MPAG (100 μM), and paclitaxel (10 μM) served as controls. Results MPAG was without effect. The AcMPAG effect on tubulin polymerization was dose dependent and significantly stronger (about 2.5-fold) than that of MPA ( n = 4; p < 0.05), but weaker than paclitaxel. Conclusions MPA and AcMPAG can induce tubulin polymerization in the presence of GTP with AcMPAG being significantly stronger. This property of AcMPAG may contribute to its IMPDH independent antiproliferative effect.

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