Cyclosporine A and Rapamycin induce in vitro cholesteryl ester transfer protein activity, and suppress lipoprotein lipase activity in human plasma.
OBJECTIVE
Cyclosporine A (CsA), Rapamycin (RAPA), Tacrolimus (FK-506) and Mycophenolate mofetil (MMF) are immunosuppressants that are widely used in solid organ transplant patients. However, some of these drugs have been reported to cause dyslipidemia in patients. Our aim was to determine the effects of these drugs on in vitro cholesteryl ester transfer protein (CETP), hepatic lipase (HL) and lipoprotein lipase (LPL) activity within human plasma.


METHODS
We measured CETP activity in human normolipidemic plasma with and without drug treatment, by measuring the incorporation of labeled cholesteryl ester into lipoproteins. To further confirm the result, we also measured recombinant CETP (rCETP) activity with and without drug treatment. We measured HL and LPL activity in post-heparin normal human plasma in the presence and absence of the drugs by measuring the release of fatty acids from radiolabeled triolein.


RESULTS
We found an increase in CETP activity in human normolipidemic plasma and rCETP treated with CsA and RAPA. By contrast, CETP activity was not altered significantly in the presence of FK-506 and MMF. LPL activity in post-heparin normal human plasma was suppressed following the co-incubation with CsA, RAPA, FK-506 or MMF whereas HL activity remained unaffected.


CONCLUSIONS
The increase in CETP activity and suppression in LPL activity following CsA and RAPA treatment observed in the present study may be associated with elevated LDL cholesterol levels and hypertriglyceridemia seen in patients administered these drugs.
Tory
Rita
R
Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Sachs-Barrable
Kristina
K
Hill
John S
JS
Wasan
Kishor M
KM
D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors; D005227:Fatty Acids / Q000737:chemistry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors* / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011994:Recombinant Proteins / Q000097:blood; D020123:Sirolimus / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D016559:Tacrolimus / Q000494:pharmacology
C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007166:Immunosuppressive Agents; D011994:Recombinant Proteins; D016572:Cyclosporine; D008071:Lipoprotein Lipase; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus