Cyclosporine A toxicity and effect of the S-adenosylmethionine

Autores/as

  • A GALÁN Department of Phisiology and Pharmacology, Universidad de Salamanca 37007 – Salamanca, Spain
  • E FERNÁNDEZ Department of Phisiology and Pharmacology, Universidad de Salamanca 37007 – Salamanca, Spain
  • A FELIPE Department of Phisiology and Pharmacology, Universidad de Salamanca 37007 – Salamanca, Spain
  • D MORÓN Department of Phisiology and Pharmacology, Universidad de Salamanca 37007 – Salamanca, Spain
  • ME MUÑOZ Department of Phisiology and Pharmacology, Universidad de Salamanca 37007 – Salamanca, Spain
  • R JIMÉNEZ Department of Phisiology and Pharmacology, Universidad de Salamanca 37007 – Salamanca, Spain

Palabras clave:

Bile acid, bile flow, cholestasis, cyclosporine A, glutathione, lipids, SAMe

Resumen

We studied the simultaneous changes undergone by the main indicators of hepatotoxicity, nephrotoxicity and diabetogenicityin rats treated with cyclosporine A (CyA) for one, two, three and four weeks, using the dose of 10 and 20 mg/kg/day.The effects of the drug on the biliary excretion of several biliary compounds as well as on the bile flow fractions -dependent and independent- of the biliary secretion of bile acids and glutathione were also studied. A further aim ofthis research was to evaluate the hepatoprotective effect of S-adenosylmethionine (SAMe) against the action of CyA. Ourresults show that CyA treatment alters hepatic, renal and pancreatic functions rapidly and simultaneously; the changeswere slightly more intense with the higher dose but they did not become more pronounced when the treatment wasprolonged for 4 weeks. The cholestatic effect of the drug is a multifactorial phenomena and develops accompanied bysimultaneous decreases in the biliary secretion of bile acids, lipid, glutathione and proteins. SAMe plus CyA cotreatmentantagonizes the main hepatotoxic effects of CyA in this species. This hepatoprotective effect of SAMe could be relatedto its regulatory function as regards membrane lipid composition and fluidity and to its key role in promoting the hepaticsynthesis of thiol compounds.

Descargas

Los datos de descargas todavía no están disponibles.

Citas

CADRA NEL, J.F., BABANY, G., OPOLON, P., ERLINGER, S.: PharmacocinZtique et effets hZpatiques de la ciclosporine A. Gastroenterol. Clin. Biol. (1992), 16: 314-321.

FAULDS, D., GOA, K.L., BENFIELD, P.: Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs (1993), 45: 953-1040.

KAHAN, B.D.: Cyclosporine. N. Engl. J. Med. (1989), 321: 1725-1738.

FARTHING, J.G., CLARK, M.L.: Nature of the toxicity of cyclosporin A in the rat. Biochem. Pharmacol. (1981), 30: 3311-3316.

STONE, B.G., UDANI, M., SANGHYI, A., WARTY, V., PLOCKI, K., BEDETTI, C.D., VAN THIEL, D.H.: Cyclosporin A-induced cholestasis. The mechanism in a rat model. Gastroenterology (1987), 93: 344-351.

WHITING, P.H., SIMPSON, J.G., DAVIDSON, R.J.L., THOMPSON, A.W. Pathological changes in rats receiving cyclosporine A at immunotherapeutic dosages for seven weeks. Br. J. Exp. Pathol. (1983), 64: 437-444.

CADRANEL, J.F., DUMONT, M., MESA, V., DEGOTT, C., TAILLANDIER, J., ERLINGER, S.: Effet de l’administration chronique de ciclosporine A sur la cholZr_se chez le rat. Gastroenterol. Clin. Biol. (1989), 13: 779-782.

CADRANEL, J.F., DUMONT, M., MESA, V.A., DEGOTT, C., TOUCHARD, D., ERLINGER, S.: Effect of chronic administration of cyclosporin A on hepatic uptake and biliary secretion of bromosulfophthalein in rat. Dig. Dis. Sci. (1991), 36: 221-224.

DURUIBE, V.A., OKONMAH, A., BLYDEN, G.T.: Effect of ciclosporin on rat liver and kidney glutathione content. Pharmacology (1989), 39: 205-212.

GALÁN, A.I., FERNÁNDEZ, E., MORÓN, D., MU„OZ, M.E., JIMÉNEZ, R.: Cyclosporine A hepatotoxicity: effect of prolonged treatment with cyclosporine on biliary lipid secretion in the rat. Clin. Exp. Pharmacol. Physiol. (1995), 22: 260-265.

MORÓN, D., GALÁN, A.I., FERNÁNDEZ, E., MORENO, C., JIMƒNEZ, R., MU„OZ, M.E.: Changes in glutathione hepatic content and ã-glutamyl-cycle enzymes during CyA long term treatment in the rat. J. Hepatol. (1995), 23 (Suppl. 1): 160.

ROMÁN, I.D., MONTE, M.J., GONZÁLEZ-BUITRAGO, J.M., ESTELLER, A., JIMƒNEZ, R.: Inhibition of hepatocytary vesicular transport by cyclosporin A in the rat: relationship with cholestasis and hyperbilirrubinemia. Hepatology (1990), 12: 83-91.

B…HME, M., M†LLER, 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: 255-265.

KADMON, M., KL†NEMAN, C., B…HME, M., ISHIKAWA, T., GORGAS, K., OTTO, G., HERFART, C., KEPPLER, D.: Inhibition by cyclosporine A of adenosine triphosphate dependent transport from the hepatocyte into bile. Gastroenterology (1993), 104: 1507-1514.

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: 974-980.

ROSSARO, L., HO, C., VAN THIEL, D.H.: 19F nuclear magnetic resonance studies of cyclosporine and model unilamellar vesicles: where does the drug sit with the membrane? Transplant. Proc. (1988), 20: 41-45.

WHITINGTON, P.F., DUDEJA, P., HECHT, J.R., WHITINGTON, S.H., BRASITUS, T.A.: Lipid alterations in the hepatocyte basolateral sinusoidal membrane (BLM) domain may explain cyclosporine (CsA) induced cholestasis in the rat. Hepatology (1988), 8: 1363.

HOFMANN, A.F.: Bile acid secretion, bile flow and biliary lipid secretion in humans. Hepatology (1990), 12: 175-255.

COLEMAN R., RAHMAN, K.: Lipid flow in bile formation. Biochim. Biophys. Acta (1992), 1125: 113-133.

LOWE, P.J., BARNWELL, S.G., COLEMAN, R.: Rapid kinetic analysis of the bile salt-dependent secretion of phospholipid, cholesterol and a plasma membrane enzyme into bile. Biochem. J. (1984), 222: 631-637.

CHANUSSOT, F., BOTTA-FRIDLUND, D., DE LA PORTE, P.L., SBARRA, V., PORTUGAL, H., PAULI, A.M., HAUTON, J., GAUTHIER, A., LAFONT, H.:

Effects of cyclosporine and corticosteroids on bile secretion in the rat. Transplantation (1992), 54: 226-231.

GALÁN, A.I., ROMÁN, I.D., MU„OZ, M.E., CAVA, F., GONZçLEZ-BUITRAGO, J.M., ESTELLER, A., JIMÉNEZ, R.: Inhibition of biliary lipid and protein secretion by ciclosporine in the rat. Biochem. Pharmacol. (1992), 44: 1105-1113.

BALLATORI, N., TRUONG, A.T.: Relation between biliary glutathione excretion and bile acid-independent bile flow. Am. J. Physiol. (1989), 256: G22-G30.

BALLATORI, N., TRUONG, A.T.: Glutathione as a primary osmotic driving force in hepatic bile formation. Am. J. Physiol. (1992), 263: G617-G624.

FERNÁNDEZ-CHECA, J.C., LU, S., OOKHTENS, M., DELEVE, L., RUNNEGAR, M., YOSHIDA, H., SAIKI, H., KANNAN, R., MADDATU, T., GARCIA-RUIZ, C., KUHLENKAMP, J., KAPLOWITZ, N.: Regulation on hepatic glutathione. In: Hepatic Transport and Bile Secretion. Physiology and Pathophysiology (1993). Pp: 363-395, eds. N. Tavoloni and P.D. Berk, Raven Press, Nueva York.

FERNÁNDEZ-CHECA, J.C., TAKIKAWA, H., HORIE, T., OOKHTENS, M., KAPLOWITZ, N.: Canalicular transport of reduced glutathione in normal and mutant Eisai hyperbilirubinemic rats. J. Biol. Chem. (1992), 267: 1667-1673.

ARIAS, I.M.: Cyclosporin, the biology of the bile canaliculus, and cholestasis. Gastroenterology (1993), 104: 1558-1560.

BALLATORI, N., DUTCZAK, W.J.: Identification and characterization of high and low affinity transport systems for reduced glutathione in liver cell canalicular membranes. J. Biol. Chem. (1994), 269: 19731-19737.

EDKINS, R.D., RYBAK, L.P., HOFFMAN, D.W.: Comparison of cyclosporine and FK506 effects on glutathione levels in rat cochlea, brain, liver and kidney. Biochem. Pharmacol. (1992), 43: 911-913.

MAYER, R.D., COCKETT, A.T.K.: Cyclosporin-mediated increase in kidney glutathione and effects on ã-glutamyl-cycle enzymes. J. Biochem. Toxicol. (1988), 3: 213-221.

ALMASIO, P., BORTOLINI, M., PAGLIARO, L., COLTORTI, M.: Role of S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis. Drugs (1990), 40 (Suppl. 3): 111-123.

BOELSTERLI, U.A., RAKHIT, G., BALAZS, T. Modulation of S-adenosyl-L-methionine of hepatic Na+,K+-ATPase, membrane fluidity, and bile flow in rats with ethinyl estradiol-induced cholestasis. Hepatology (1983), 3: 12-17.

FRICKER, G., LANDMANN, L., MEIER, P.J. Ethynil-estradiol (EE) induced structural and functional alterations of rat liver plasma membranes and their reversal by S-adenosyl-L-methionine (SAMe) in vitro. Hepatology (1988), 8: 1224.

FRIEDEL, H.A., GOA, K.L., BENFIELD, P.: S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs (1989), 38: 389-416.

FERNÁNDEZ, E., MU„OZ, M.E., ROMçN, I.D., GALçN, A.I., GONZçLEZ-BUITRAGO, J.M., JIMƒNEZ, R.: Cyclosporin A-induced cholestasis in the rat. Beneficial effects of S-adenosyl-L-methionine. Drug Invest. (1992), 4 (Suppl. 4): 54-63.

FERNÁNDEZ, E., GALÁN, A.I., MORçN, D., GONZÁLEZ-BUITRAGO, J.M., MUÑOZ, M.E., JIMÉNEZ, R.: Reversal of cyclosporine A-induced alterations in biliary secretion by S-adenosyl-L-methionine in rats. J. Pharmacol. Exp. Ther. (1995), 275: 442-449.

CORRALES, F., GIMÉNEZ, A., ÁLVAREZ, L., CABALLERÍA, J., PAJARES, M.A., ANDREU, A., MATO, J.M., RODÉS, J.: S-adenosylmethionine treatment prevents carbon tetrachloride-induced S-adenosylmethionine synthetase inactivation and atenuates liver injury. Hepatology (1992), 16: 1022-1027.

GARCÍA-RUIZ, C., MORALES, A., COLELL, A., BALLESTA, A., RODÉS, J., KAPLOWITZ, N., FERNÁNDEZ-CHECA, J.C.: Feeding S-adenosyl-l-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes. Hepatology (1995), 21: 207-214.

JOVER, R., PONSODA, X., FABRA, R., TRULLENQUE, R., GîMEZ-LECHîN, M.J., CASTELL, J.V.: S-adenosyl-Lmethionine prevents intracellular glutathione depletion by GSH-depleting drugs in rat and human hepatocytes. Drug Invest. (1992), 4 (Suppl. 4): 46-53.

SZTEFKO, K., LI, P., BALLATORI, N., CHEY, W.Y.: CCK-receptor antagonists proglumide and loxiglumide stimulate bile flow and biliary glutathione excretion. Dig. Dis. Sci. (1994), 39: 1974-1980.

GRIFFITH, O.W.: Determination of glutathione and glutathione disulfide using gutathione reductase and 2-vinylpyridine. Anal. Biochem. (1980), 106: 207-212.

TIETZE, F.: Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal. Biochem. (1969), 27: 502-522.

WHITING, P.H., THOMPSON, A.W., SIMPSON, J.G. Cyclosporine: toxicity, metabolism and drug interactions-implications from animal studies. Transplant. Proc. (1985), 17: 134-144.

EL-NAGGERE, M., BOUCHARD, G., TUCHWEBER, B., YOUSEF, I.M.: Partial protection by taurocholic and ursodeoxycholic acids of cyclosporin A-induced cholestasis in isolated perfused rat liver. Gastroenterology (1995), 108: A1062.

SAUER, P., KL…TERS-PLACHKY, P., GUTZLER, F., KOMMERELL, B., STIEHL, A.: Cyclosporin A inhibits the active absorption of bile acids in the ileum of the rat. XII International Bile Acid Meeting, Basel (1992): 26.

ZIEGLER, K., POLZIN, G., FRIMMER, M. Hepatocellular uptake of cyclosporin A by simple diffusion. Biochim. Biophys. Acta (1988), 938: 44-50.

LE GRUE, S.J., FRIEDMAN, A.W., KAHAN, B.D.: Binding of cyclosporine by human lymphocytes and phospholipid vesicles. J. Immunol. (1983), 131: 712-718.

MEHTA, M.U., VENKATARAMANAN, R., BURCKART, G.J., PTACHCINSKI, R.J., DELAMOS, B., STACHAK, S., VAN THIEL, D.H., IWATSUKI, S., STARZL, T.E.: Effect of bile on cyclosporin absorption in liver transplant

patients. Br. J. Clin. Pharmacol. (1988), 25: 579-584.

BALLATORI, N., JACOB, R., BARRETT, C., BOYER, J.L. Biliary catabolism of glutathione and differential reabsorption of its amino acid constituents. Am. J. Physiol. (1988), 254: G1-G7.

BOUCHARD, G., YOUSEF, I.M., TUCHWEBER, B.: Decreased biliary glutathione content is responsible for the decline in bile salt-independent flow induced by ethinyl estradiol in rats. Toxicol. Lett (1994), 74: 221-233.

MOHAN, P., LING, S.C., WATKINS, J.B.: Ontogeny of hepatobiliary secretion: role of glutathione. Hepatology (1994), 19: 1504-1512.

ERLINGER, S.: Bile flow. In: The Liver: Biology and Pathobiology (1994). Pp: 769-786, eds. I.M. Arias, J.L. Boyer, N.Fausto, W.B. Jacoby, D. Schachter and D.A. Shafritz, Raven Press, Nueva York.

HARDISON, W.G.M.: Hepatocellular tight junctions. Role of canalicular permeability in hepatobiliary transport. In: Hepatic Transport and Bile Secretion: Physiology and Pathophysiology (1993). Pp. 571-587, eds. N. Tavoloni and P.D. Berk, Raven Press, New York.

DELEVE, L.D., KAPLOWITZ, N.: Importance and regulation of hepatic glutathione. Semin. Liver Dis. (1990), 10: 251-266.

LAUTERBURG, B.H.: Biliary excretion of glutathione and glutathione adducts. Progr. Pharmacol. Clin. Pharmacol. (1991), 8: 201-213.

Descargas

Publicado

1999-06-20

Cómo citar

1.
GALÁN A, FERNÁNDEZ E, FELIPE A, MORÓN D, MUÑOZ M, JIMÉNEZ R. Cyclosporine A toxicity and effect of the S-adenosylmethionine. Ars Pharm [Internet]. 20 de junio de 1999 [citado 2 de mayo de 2024];40(3):151-63. Disponible en: https://revistaseug.ugr.es/index.php/ars/article/view/5762

Número

Vol. 40 Núm. 3 (1999)

Sección

Artículos Originales

Licencia

Los artículos que se publican en esta revista están sujetos a los siguientes términos en relación a los derechos patrimoniales o de explotación:

  1. Los autores/as conservarán sus derechos de autor y garantizarán a la revista el derecho de primera publicación de su obra, la cual se distribuirá con una licencia Creative Commons BY-NC-SA  4.0 que permite a terceros reutilizar  la obra siempre que se indique su autor, se cite la fuente original y no se haga un uso comercial de la misma.
  2. Los autores/as podrán adoptar otros acuerdos de licencia no exclusiva de distribución de la versión de la obra publicada (p. ej.: depositarla en un archivo telemático institucional o publicarla en un volumen monográfico) siempre que se indique la fuente original de su publicación.
  3. Se permite y recomienda a los autores/as difundir su obra a través de Internet (p. ej.: en repositorios  institucionales o en su página web) antes y durante el proceso de envío, lo cual puede producir intercambios interesantes y aumentar las citas de la obra publicada. (Véase El efecto del acceso abierto).