Peteherych K D, Wasan K M
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
J Pharm Sci. 2001 Sep;90(9):1395-406. doi: 10.1002/jps.1092.
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.
环孢素A（CSA）是一种有效的免疫抑制剂，但诸如肾毒性等副作用会限制其治疗用途。目前的研究调查了脂蛋白对猪上皮细胞系LLC-PK(1)中CSA诱导的肾毒性的影响。在LLC-PK(1)细胞系中，蛋白质合成和氚标记的CSA分别被用作毒性和CSA摄取的指标。测试了处于低脂、正常血脂和高脂血症水平的三种主要脂蛋白类别，即极低密度脂蛋白（VLDL）、低密度脂蛋白（LDL）和高密度脂蛋白（HDL）影响CSA诱导的毒性和摄取的能力。还测试了每种脂蛋白的主要成分以确定其对CSA诱导的毒性和摄取的影响。HDL的主要蛋白质成分载脂蛋白A-I（ApoA-I）和完整的LDL颗粒对CSA摄取和毒性的影响最为显著。随着LDL浓度升高，CSA的摄取和毒性有效降低，但与升高浓度的ApoA-I孵育时则显著增加（p < 0.05）。增加VLDL和HDL浓度可略微降低CSA毒性和摄取，但随着孵育时间延长影响不大。VLDL和LDL各自的主要成分甘油三酯和胆固醇在测试条件下未改变CSA摄取或毒性。LDL和ApoA-I被确定为LLC-PK(1)细胞中CSA毒性和摄取的主要效应物。这些效应可能通过诸如LDL受体或参与蛋白质重吸收的受体介导。此处呈现的数据清楚地证明了CSA诱导的毒性与相关脂蛋白性质之间的关系。
