Effect of cyclosporine A on the binding affinity and internalization of low-density lipoproteins in human skin fibroblasts.
The aim of this study was to elucidate the possible causes of elevated low-density lipoprotein (LDL)-cholesterol levels in patients with transplants who were treated with the immunosuppressant drug cyclosporine A (CSA). The binding and internalization of (125)I-LDL in the presence or absence of CSA at varying concentrations (5-15 microg/mL) within human skin fibroblasts were determined. In addition, the effect of LDL-associated CSA on the binding of LDL to its receptor was determined. CSA decreases LDL internalization without altering the extent and affinity of its binding to the LDL receptor. CSA did not alter the number of available LDL binding sites. Furthermore, the association of CSA with LDL did not affect the binding affinity of LDL to its receptor, suggesting that this binding may not be a mechanism by which CSA affects the subsequent clearance of LDL from the bloodstream. These findings suggest that CSA may cause an increase in plasma LDL-cholesterol in patients with transplants, thereby inhibiting LDL particle internalization without altering LDL receptor binding.
Wasan
Kishor M
KM
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. kwasan@interchange.ubc.ca
Donnachie
Elizabeth M
EM
Seccombe
David W
DW
Pritchard
P Haydn
PH
D016572:Cyclosporine / Q000378:metabolism* / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D008077:Lipoproteins, LDL; D016572:Cyclosporine