Cyclosporine inhibits catabolism of low-density lipoproteins in HepG2 cells by about 25%

Abstract

Cyclosporine is today one of the most widely used immuno-SEE EDITORIAL ON PAGE 735 suppressive drugs and used in most transplantation centers to prevent organ rejection. It is a cyclic polypeptide, consisting of 11 amino acids and has a molecular weight of 1,202 The aim of this study was to elucidate the possible d. It is insoluble in water but soluble in many organic solcauses of elevated low-density lipoprotein (LDL)-choles-vents, and it is thus a lipophilic drug. Cyclosporine selectively terol levels in transplanted patients treated with the im-inhibits the interleukin-2-driven proliferation of activated T munosuppressant drug, cyclosporine. HepG2 cells, from lymphocytes with a subsequent suppression of proliferation a well-differentiated cell-line of hepatoma cells, were and generation of cytotoxic T lymphocytes, while sparing cultured and used as a model for in vitro hepatocytic T-suppressor-cell subpopulations. Patients, who are liver LDL uptake. Different concentrations of cyclosporine, transplant recipients and use this drug to prevent organ rewhich were within the range of concentrations found in jection are, however, prone to be afflicted by cardiovascular humans treated with cyclosporine, were added to tissue disease due to the development of atherosclerosis and atherculture medium together with 125 I-LDL. The results oma formation, a result of cyclosporine-caused elevation of showed that cyclosporine reduced LDL uptake and deg-blood low-density lipoprotein (LDL)-cholesterol levels. 1-5 radation in HepG2 cells by about 25%. The cells wereThe mechanism whereby cyclosporine causes high LDLalso pretreated with cyclosporine for 1 to 24 hours and cholesterol levels to occur has not yet been clarified. Due to then incubated with new medium containing labeled its hydrophobic property, cyclosporine binds to lipoproteins LDL for 2 hours at 4ЊC in an LDL-binding assay. The and in plasma is bound to high-density lipoproteins (33%-data showed that cyclosporine reduced the subsequent 46%), to low-density lipoproteins (28%-35%), and to very-low-LDL binding. Cyclosporine has no toxic effects on HepG2 density lipoproteins (VLDL) (6%-19%) 6,7 ; therefore, lipoprocells, as shown by unchanged growth capacity of the teins act as carriers for cyclosporine. cells. By means of a 50-fold excess of unlabeled LDL,Lipoproteins, according to their densities, are categorized a monoclonal anti-LDL receptor antibody, and dextran into chylomicrons, chylomicron remnants, VLDL, intermedisulfate, we also evaluated if this inhibition of LDL bind-ate-density lipoproteins, LDL, and high-density lipoproteins. ing occurred through the LDL receptor-mediated path-VLDL and LDL are the major cholesterol carriers in the way, through non-LDL receptor-mediated pathways, or blood. VLDL is secreted from the intestine and the liver. 8 through both. The results show that cyclosporine re-Liver-derived VLDL is converted to LDL, and this conversion duces LDL binding and uptake by mainly inhibiting the is primarily mediated by the enzyme lipoprotein li...

Improved Cardiovascular Risk Profile and Renal Function in Renal Transplant Patients after Randomized Conversion from Cyclosporine to Tacrolimus

“…Cyclosporine increases serum LDL cholesterol level by inhibiting the synthesis of LDL receptors in the liver, thereby interfering with the LDL receptor-mediated catabolism in the liver (20). The improvement in serum LDL cholesterol level after conversion to tacrolimus might be due to the withdrawal of this inhibition of the LDL receptor production.…”

Reversal of cyclosporine-inhibited low-density lipoprotein receptor activity in HepG2 cells by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

“…The same concentration of ethanol was added to the control activated T lymphocytes, while sparing T-suppressor cell sub-groups. 9 Fluvastatin was dissolved in water. Compactin was a gift populations.…”

“…AID Hepa 0004 / 5p1e$$$$62 03-11-97 00:36:46 hpta WBS: Hepatology down-regulates the LDL receptor binding. 9 Our question now is, if cyclosporine down-regulates LDL binding in cells where LDL receptor activity has been up-regulated by HMG-CoA reductase inhibitors. As Fig.…”

“…9 In several clinical trials, different 3-hylow-density lipoprotein (LDL) catabolism in HepG2 cells.droxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase This inhibition mainly occurs through reduced LDL-reinhibitors have been used to treat cyclosporine-induced hyceptor activity. 3-Hydroxy-3-methylglutarylcoenzyme A perlipidemia in transplanted patients.…”

“…9 In several clinical trials, different 3-hylow-density lipoprotein (LDL) catabolism in HepG2 cells.…”