The effect of lipoproteins association on cyclosporine metabolism and toxicity in rats

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2002

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Kim, Taek-rho

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Abstract

Based on the hypothesis that the therapeutic and toxic effects of cyclosporine (CSA) are dependent on the in vivo disposition of lipoprotein-associated drug, we examined the metabolic effect and toxicity of lipoprotein-associated CSA. We also explored the regulatory effect of low density lipoprotein receptors (LDL-R) on CSA metabolism. A 10 mg/kg/d IV CSA dose for 14 days reduced CYP3A protein and activities in all lipoprotein-associated CSA groups, with the exception of the very low density lipoprotein (VLDL)-CSA group. This reduction was attributed to a decrease in CYP3A1/2 mRNA levels. VLDL-CSA showed no changes in CYP3A levels as compared with CSA alone, suggesting a possible delay of CSA exposure to the liver. Furthermore, VLDL-CSA did not alter lipoprotein receptors mRNA, while LDL-CSA caused a significant suppression of LDL-R. However, scavenger receptor class B type I (SR-BI) was not altered by CSA treatment. The suppression of CYP3A and CYP2C11 is more obvious when low dose (0.1 mg/kg/d) was given, suggesting an enhanced uptake of CSA into liver by LDL-R. The specific role of LDL-R was examined with LDL-R modified rat model by either 17a-ethynylestradiol (EE) or 2% cholesterol diet. A 28 days of 15 mg/kg/d CSA SC treatment in LDL-R suppressed rats (mimic LDL-R saturated rats by chronic CSA dose) showed a decreased suppression of CYP3A, which caused an increase in availability of CSA to other tissues such as kidney and which led to an induction of renal LDL-R. In contrast, LDL-R induced rats showed the opposite results. This study also showed that the regulation of LDL-R is sexually dimorphic and tissue-dependent. In addition, CSA caused the induction of LDL-R due to, in part, the presence of growth hormone (GH) and an altered GH pattern of secretion. Taken together, these results demonstrated lipoproteins caused varying hepatic metabolic responses that were partially attributed to hepatic LDL-R on CSA metabolism. In addition, induction of renal LDL-R resulted in CSA-induced renal toxicity. CSA caused the saturation of LDL-R in the liver partially due to GH, which leads to the stimulation of an LDL-R-independent pathway to increase plasma lipid levels. The present study offers a better understanding of changes occurring in lipoprotein metabolism and immunosuppressant effects in transplant patients.

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