Effects of Curcumin on Cyclosporine-Induced Cholestasis and Hypercholesterolemia and on Cyclosporine Metabolism in the Rat

 

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Abstract

Former studies have shown that curcumin, which can be extracted from different Curcuma species, is able to stimulate bile flow and to reduce hypercholesterolemia. We investigated in a subchronic bile fistula model the ability of curcumin to reduce cyclosporine-induced cholestasis and hypercholesterolemia. Male Wistar rats were daily treated with curcumin (100 mg/kg p. o.), cyclosporine (10 mg/kg i. p.), and a combination of curcumin with cyclosporine. After two weeks a bile fistula was installed into the rats to measure bile flow and biliary excretion of bile salts, cholesterol, bilirubin, cyclosporine and its main metabolites. Blood was taken to determine the concentration of these parameters in serum or blood. Cyclosporine reduced bile flow (-14 %) and biliary excretion of bile salts (-10 %) and cholesterol (-61 %). On the other hand, cyclosporine increased serum concentrations of cholesterol and triglycerides by 32 % and 82 %, respectively. Sole administration of curcumin led to a slight decrease of bile flow (-7 %) and biliary bile salt excretion (-12 %), but showed no effect on biliary excretion of cholesterol and serum lipid concentration. When curcumin was given simultaneously with cyclosporine, the cyclosporine-induced cholestasis was enhanced but the cyclosporine-induced hyperlipidemia was not affected. Neither the biliary excretion nor the blood concentration of cyclosporine was influenced by curcumin. The blood concentration of the main cyclosporine metabolites, however, was lowered by half while their biliary excretion was strongly increased by curcumin. From these results we conclude that curcumin is not able to prevent cyclosporine-induced cholestasis and hyperlipidemia after prolonged administration in bile fistula rats.

Abbreviations

Bsep:bile salt export pump

CD28: cluster of differentiation 28

Cps:millipascal seconds

GSH:reduced glutathione

HDL:high-density lipoproteins

HPLC:high-performance liquid chromatography

i. p.:intraperitoneally

LDL:low-density lipoproteins

Mrp2: multidrug resistance protein 2

Ntcp:Na⁺/taurocholate cotransporting polypeptide

Oatp:  organic anion transporting polypeptide

PE:polyethylene

Pgp:P-glycoprotein

p. o.:peroral

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Dr. Michael Deters

Institut für Pharmakologie

Medizinische Hochschule Hannover

Carl-Neuberg-Str. 1

30625 Hannover

Germany

Phone: +49-511-532-2798

Fax: +49-511-532-8798

Email: Michael.Deters@solvay.com