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DOI: 10.1055/s-2003-38870
© Georg Thieme Verlag Stuttgart · New York
Effects of Curcumin on Cyclosporine-Induced Cholestasis and Hypercholesterolemia and on Cyclosporine Metabolism in the Rat
Publication History
Received: August 8, 2002
Accepted: October 26, 2002
Publication Date:
23 April 2003 (online)
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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
Key words
cholestasis - curcumin - Curcuma spec. - Cyclosporine - Hypercholesterolemia - Zingiberaceae
References
- 1 Burke J F, Pirsch J D, Ramos E L, Salomon D R, Stablein D M, Van Buren D H, West J C. Long-term efficacy and safety of cyclosporine in renal-transplant recipients. N Engl J Med. 1994; 331 358-63
- 2 Lorber M I, Van Buren C T, Lechner S M, Williams C, Kahan B D. Hepatobiliary and pancreatic complications of cyclosporine therapy in 466 renal transplant recipients. Transplantation. 1987; 43 35-40
- 3 Deters M, Strubelt O, Younes M. Reevaluation of cyclosporine induced hepatotoxicity in the isolated perfused rat liver. Toxicology. 1997; 123 197-206
- 4 Groth C G, Backman L, Morales J M, Calne R, Kreis H, Lang P, Touraine J L, Claesson K, Campistol J M, Durand D, Wramner L, Brattstrom C, Charpentier B. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation. 1999; 67 1036-42
- 5 Deters M, Siegers C, Muhl P, Hansel W. Choleretic effects of curcuminoids on an acute cyclosporin-induced cholestasis in the rat. Planta Med. 1999; 65 610-3
- 6 Deters M, Siegers C, Hansel W, Schneider K P, Hennighausen G. Influence of curcumin on cyclosporin-induced reduction of biliary bilirubin and cholesterol excretion and on biliary excretion of cyclosporin and its metabolites. Planta Med. 2000; 66 429-34
- 7 Soni K B, Kuttan K. Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers. Indian J Physiol Pharmacol. 1992; 36 273-5
- 8 Ranjan D, Johnston T D, Wu G, Elliott L, Bondada S, Nagabushan M. Curcumin blocks cyclosporine A-resistant CD28 costimulatory pathway of human T-cell proliferation. J Surg Res. 1998; 77 174-8
- 9 Deters M, Klabunde T, Kirchner G, Resch K, Kaever V. Sirolimus/cyclosporine/tacrolimus interactions on bile flow and biliary excretion of immunosuppressants in a subchronic bile fistula rat model. B J Pharmacol. 2002; 136 604-12
- 10 Christians U, Zimmer K O, Wonigeit K, Maurer G, Sewing K F. Liquid chromatographic measurement of cyclosporine A and its metabolites in blood, bile and urine. Clin Chem. 1988; 34 34-9
- 11 CONSENSUS DOCUMENT. Hawk's Cay meeting on the therapeutic drug monitoring of cyclosporine. Transplant Proc 1999 22: 1357-61
- 12 Moseley R H, Johnson T R, Morrissette J M. Inhibition of bile acid transport by cyclosporine A in rat liver plasma membrane vesicles. J Pharmacol Exp Ther. 1990; 253 974-80
- 13 Meier P J, Stieger B. Bile salt transporters. Annu Rev Physiol. 2002; 64 635-61
- 14 Stacey N H, Kotecka B. Inhibition of taurocholate and ouabain transport in isolated rat hepatocytes by cyclosporin A. Gastroenterology. 1988; 95 780-6
- 15 Böhme M, Müller M, Leier I, Jedlitschky G, Keppler D. Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver. Gastroenterology. 1994; 107 255-65
- 16 Paulusma C C, van Geer M A, Evers R, Heijn M, Ottenhoff R, Borst P, Oude Elferink R P. Canalicular multispecific organic anion transporter/multidrug resistance protein 2 mediates low-affinity transport of reduced glutathione. Biochem J. 1999; 338 393-401
- 17 Moran D, De Buitrago J M, Fernandez S M, Galan A I, Munoz M E, Jimenez R. Inhibition of biliary glutathione secretion by cyclosporine A in the rat: possible mechanisms and role in the cholestasis induced by the drug. J Hepatol. 1998; 29 68-77
- 18 Graham J, Ahmed H, Northfield T C. Unidirectional pathway of vesicular cholesterol transport. In: Trends in Bile Salt Research. Paumgartner G, Dordrecht, editors New York; Kluwer 1989: pp. 177-87
- 19 Galan A I, Fernandez S M, Moran D, Munoz M E, Jimenez R. Cyclosporine A hepatotoxicity: effect of prolonged treatment with cyclosporine on biliary lipid secretion in the rat. Clin Exp Pharmacol Physiol. 1995; 22 260-5
- 20 Li D, Zimmerman T L, Thevananther S, Lee H Y, Kurie J M, Karpen S J. Interleukin-1beta-mediated suppression of RXR:RAR transactivation of the Ntcp promoter is JNK-dependent. J Biol Chem. 2002; 277 31 416-22
- 21 Romiti N, Tongiani R, Cervelli F, Chieli E. Effects of curcumin on P-glycoprotein in primary cultures of rat hepatocytes. Life Sci. 1998; 62 2349-58
- 22 Sambaiah K, Srinivasan K. Influence of spices and spice principles on hepatic mixed function oxygenase system in rats. Indian J Biochem Biophys. 1989; 26 254-8
- 23 Oetari S, Sudibyo M, Commandeur J N, Samhoedi R, Vermeulen N P. Effects of curumin on cytochrome P450 and glutathione S-transferase activities in rat liver. Biochem Pharmacol. 1996; 51 39-45
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