The interaction between lipid derivatives of colchicine and tubulin: consequences of the interaction of the alkaloid with lipid membranes.
Colchicine is a potent antimitotic poison which is well known to prevent microtubule assembly by binding tubulin very tightly. Colchicine also possesses anti-inflammatory properties which are not well understood yet. Here we show that colchicine tightly interacts with lipid layers. The physical and biological properties of three different lipid derivatives of colchicine are investigated parallel to those of membrane lipids in the presence of colchicine. Upon insertion in the fatty alkyl chains, colchicine rigidifies the lipid monolayers in a fluid phase and fluidifies rigid monolayers. Similarly X-ray diffraction data show that lecithin-water phases are destabilized by colchicine. In addition, an unexpectedly drastic enhancement of the photoisomerization rate of colchicine into lumicolchicine in the lipid environment is observed and further supports insertion of the alkaloid in membranes. Finally the interaction of colchicine with lipids makes the drug inaccessible to tubulin. The possible in vivo significance of these results is discussed.
Mons
S
S
Laboratoire de Synthese Bioorganique associe au CNRS, Universite Louis pasteur de Strasbourg, 67401 Illkirch, France.
Veretout
F
F
Carlier
M
M
Erk
I
I
Lepault
J
J
Trudel
E
E
Salesse
C
C
Ducray
P
P
Mioskowski
C
C
Lebeau
L
L
D003078:Colchicine / Q000031:analogs & derivatives*; D003460:Crystallization; D020558:GTP Phosphohydrolases / Q000737:chemistry; D007536:Isomerism; D008051:Lipid Bilayers / Q000737:chemistry; D008563:Membrane Lipids / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D011108:Polymers; D012997:Solvents; D014404:Tubulin / Q000031:analogs & derivatives*; D014961:X-Ray Diffraction
D008051:Lipid Bilayers; D008563:Membrane Lipids; D011108:Polymers; D012997:Solvents; D014404:Tubulin; D020558:GTP Phosphohydrolases; D003078:Colchicine