Cyclosporine binds to the neutral lipid and potentially other binding sites of lipid transfer protein I.
OBJECTIVE
The objective of this study was to determine if cyclosporine (CSA) binds directly to the neutral lipid-binding site of lipid transfer protein I (LTP I).


METHODS
This was accomplished by determining LTP I concentrations and cholesteryl esters (CE) and CSA radioactivity of eluted fast protein liquid chromatography (FPLC) fractions following an injection of different treatment groups (i.e., LTP I alone, 3H-CE liposomes alone, 3H-CSA liposomes alone, 3H-CE liposomes + LTP I, and 3H-CSA liposomes + LTP I) onto an FPLC column. Our hypothesis is that CSA will bind to the neutral lipid-binding site of LTP I because of its high solubility/interaction with cholesterol and triglycerides.


RESULTS
Coincubation of LTP I with 3H-CE liposomes resulted in a significant decrease in the LTP I peak reported at fraction 10 and the appearance of a broad LTP I peak at fractions 30-34 compared to control. Coincubation of LTP I with 3H-CSA liposomes resulted in a significant decrease in the LTP I peak reported at fraction 10 and fraction 30 compared to control. In addition, 30% of the original radioactivity associated with 3H-CSA liposomes was found coeluted with the unbound LTP I peak at fraction 10. Taken together, these findings suggest that CSA does bind to the neutral lipid-binding site of LTP I but may also bind to other regions along the LTP I molecule.


CONCLUSIONS
We have determined that LTP I mediated transfer of CSA between lipoproteins may be a result of the direct binding of CSA to LTP I at both its neutral binding site and potentially other binding sites along the molecule. These findings provide further evidence that the distribution/redistribution of drugs among plasma lipoproteins facilitated by LTP I may serve as a possible mechanism for determining the ultimate fate of drug compounds.
Kwong
Mona
M
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Wasan
Kishor M
KM
D000704:Analysis of Variance; D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D016572:Cyclosporine / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins; D006801:Humans
D002352:Carrier Proteins; D050556:Fatty Acid-Binding Proteins; C422456:Ltp1 protein, barley; D016572:Cyclosporine