The effects of lipoproteins on cyclosporine A toxicity and uptake in renal cells

Cyclosporine A (CSA) is an effective immunosuppressant, but side effects such as renal toxicity can limit its therapeutic use. The hydrophobicity of CSA results in significant association of the drug with lipoproteins in the blood. Lipid levels in patients undergoing CSA therapy are correlated wi...

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Main Author: Peteherych, Kathy Dawn
Format: Others
Language:English
Published: 2009
Online Access:http://hdl.handle.net/2429/10725
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spelling ndltd-UBC-oai-circle.library.ubc.ca-2429-107252018-01-05T17:35:28Z The effects of lipoproteins on cyclosporine A toxicity and uptake in renal cells Peteherych, Kathy Dawn Cyclosporine A (CSA) is an effective immunosuppressant, but side effects such as renal toxicity can limit its therapeutic use. The hydrophobicity of CSA results in significant association of the drug with lipoproteins in the blood. Lipid levels in patients undergoing CSA therapy are correlated with CSA-induced renal toxicity. Renal damage in the glomerulus, the site of blood filtration, results in increased lipoprotein leakage into the proximal tubule, a major site of CSA toxicity. The current studies investigate the effects of lipoproteins on CSA-induced renal toxicity in the pig epithelial cell line LLC-PK1. Toxicity and uptake of CSA in the LLC-PK1 cell line were measured by protein synthesis and tritiated CSA, respectively. The three main classes of lipoproteins, very low (VLDL), low (LDL) and high density lipoproteins (HDL) at hypo-, normo- and hyperlipidemic levels were tested for their ability to affect CSA-induced toxicity and uptake. The major component of each lipoprotein was also tested to determine its effects on CSA-induced toxicity and uptake. The involvement of lipoprotein receptors as determinants in mediating toxicity was also examined. ApoA-I, the major protein component of HDL, and intact LDL particles showed the most significant effects on CSA uptake and toxicity. The uptake and toxicity of CSA was effectively reduced with elevated LDL concentrations but showed a significant increase (p<0.05) when incubated with elevated concentrations of apoA-I. Increasing VLDL and HDL concentrations slightly reduced CSA toxicity and uptake, but showed little effect with increased incubation time. Triglyceride and cholesterol, the respective major components of VLDL and LDL did not alter CSA uptake or toxicity under the conditions tested. LDL and apoA-I are identified as the major effectors of CSA toxicity and uptake in LLC-PK1 cells. These effects may be mediated through receptors such as the LDL receptor or those involved in protein re-absorption. The data presented here clearly demonstrate a relationship between CSA-induced toxicity and the nature of the associated lipoprotein. Careful monitoring of lipid levels in patients undergoing CSA therapy may improve patient care and minimize CSA-induced toxicity in the kidney. Pharmaceutical Sciences, Faculty of Graduate 2009-07-13T19:45:17Z 2009-07-13T19:45:17Z 2000 2000-11 Text Thesis/Dissertation http://hdl.handle.net/2429/10725 eng For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. 4439818 bytes application/pdf
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description Cyclosporine A (CSA) is an effective immunosuppressant, but side effects such as renal toxicity can limit its therapeutic use. The hydrophobicity of CSA results in significant association of the drug with lipoproteins in the blood. Lipid levels in patients undergoing CSA therapy are correlated with CSA-induced renal toxicity. Renal damage in the glomerulus, the site of blood filtration, results in increased lipoprotein leakage into the proximal tubule, a major site of CSA toxicity. The current studies investigate the effects of lipoproteins on CSA-induced renal toxicity in the pig epithelial cell line LLC-PK1. Toxicity and uptake of CSA in the LLC-PK1 cell line were measured by protein synthesis and tritiated CSA, respectively. The three main classes of lipoproteins, very low (VLDL), low (LDL) and high density lipoproteins (HDL) at hypo-, normo- and hyperlipidemic levels were tested for their ability to affect CSA-induced toxicity and uptake. The major component of each lipoprotein was also tested to determine its effects on CSA-induced toxicity and uptake. The involvement of lipoprotein receptors as determinants in mediating toxicity was also examined. ApoA-I, the major protein component of HDL, and intact LDL particles showed the most significant effects on CSA uptake and toxicity. The uptake and toxicity of CSA was effectively reduced with elevated LDL concentrations but showed a significant increase (p<0.05) when incubated with elevated concentrations of apoA-I. Increasing VLDL and HDL concentrations slightly reduced CSA toxicity and uptake, but showed little effect with increased incubation time. Triglyceride and cholesterol, the respective major components of VLDL and LDL did not alter CSA uptake or toxicity under the conditions tested. LDL and apoA-I are identified as the major effectors of CSA toxicity and uptake in LLC-PK1 cells. These effects may be mediated through receptors such as the LDL receptor or those involved in protein re-absorption. The data presented here clearly demonstrate a relationship between CSA-induced toxicity and the nature of the associated lipoprotein. Careful monitoring of lipid levels in patients undergoing CSA therapy may improve patient care and minimize CSA-induced toxicity in the kidney. === Pharmaceutical Sciences, Faculty of === Graduate
author Peteherych, Kathy Dawn
spellingShingle Peteherych, Kathy Dawn
The effects of lipoproteins on cyclosporine A toxicity and uptake in renal cells
author_facet Peteherych, Kathy Dawn
author_sort Peteherych, Kathy Dawn
title The effects of lipoproteins on cyclosporine A toxicity and uptake in renal cells
title_short The effects of lipoproteins on cyclosporine A toxicity and uptake in renal cells
title_full The effects of lipoproteins on cyclosporine A toxicity and uptake in renal cells
title_fullStr The effects of lipoproteins on cyclosporine A toxicity and uptake in renal cells
title_full_unstemmed The effects of lipoproteins on cyclosporine A toxicity and uptake in renal cells
title_sort effects of lipoproteins on cyclosporine a toxicity and uptake in renal cells
publishDate 2009
url http://hdl.handle.net/2429/10725
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