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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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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English |
format |
Others
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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 |
work_keys_str_mv |
AT peteherychkathydawn theeffectsoflipoproteinsoncyclosporineatoxicityanduptakeinrenalcells AT peteherychkathydawn effectsoflipoproteinsoncyclosporineatoxicityanduptakeinrenalcells |
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1718588642468823040 |