Effects of lipoproteins on cyclosporine A toxicity and uptake in LLC-PK1 pig kidney cells.
Cyclosporine A (CSA) is an effective immunosuppressant, but side effects such as renal toxicity can limit its therapeutic use. The current studies investigate the effects of lipoproteins on CSA-induced renal toxicity in the pig epithelial cell line LLC-PK(1). Protein synthesis and tritiated CSA were used as measures of toxicity and uptake of CSA, respectively, in the LLC-PK(1) cell line. 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. ApoA-I, the major protein component of HDL, and intact LDL particles showed the most significant effects of 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-PK(1) cells. These effects may be mediated through receptors such as the LDL receptor or those involved in protein reabsorption. The data presented here clearly demonstrate a relationship between CSA-induced toxicity and the nature of the associated lipoprotein.
Peteherych
K D
KD
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Wasan
K M
KM
D000818:Animals; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D018374:LLC-PK1 Cells / Q000187:drug effects* / Q000378:metabolism*; D008074:Lipoproteins / Q000494:pharmacology*; D013552:Swine
D007166:Immunosuppressive Agents; D008074:Lipoproteins; D016572:Cyclosporine