INVESTIGADORES
SANCHEZ POZZI Enrique Juan
artículos
Título:
Beneficial effects of silymarin on estrogen-induced cholestasis in the rat. A study in vivo and in isolated hepatocyte couplets
Autor/es:
A CROCENZI, FERNANDO; ENRIQUE JUAN SANCHEZ POZZI; M PELLEGRINO, JOSÉ; FAVRE, CRISTIAN O; RODRÍGUEZ GARAY, EMILIO A; D MOTTINO, ALDO; ROGER COLEMAN,; G ROMA, MARCELO
Revista:
HEPATOLOGY
Editorial:
John Willey and Sons
Referencias:
Año: 2001 vol. 34 p. 329 - 339
ISSN:
0171-6123
Resumen:
The effect of silymarin (SIL) on 17-ethynylestradiol (EE)-induced cholestasis was evaluated in rats. EE (5 mg/kg, subcutaneously, daily, for 5 days) decreased both the bile salt?dependent and the bile-salt?independent fractions of the bile flow. The decrease in the former was associated to a reduction in the bile salt pool size (58%), and this effect was completely prevented by SIL. This compound also counteracted the inhibitory effect induced by EE on HCO3 but not glutathione output, 2 major determinants of the bile-salt?independent bile flow. EE decreased the secretory rate maximum (SRM) of tauroursodeoxycholate, (71%) and bromosulfophthalein (BSP; 60%), as well as the expression of the BSP canalicular carrier, mrp2; SIL failed to increase mrp2 expression, and had only a marginal beneficial effect on both tauroursodeoxycholate and BSP SRM values.However, the two-compartment model-based kinetic constant for BSP canalicular transfer was significantly improved by SIL (262%). SIL decreased rather than increased CYP3A4, the cytochrome P450 isoenzyme involved in the oxidative metabolism of EE, and had no inhibitory effect on the UDP-glucuronosyltrasferase isoforms involved in the formation of its 17-glucuronidated,more cholestatic metabolite. Pretreatment of isolated rat hepatocyte couplets with silibinin, the major, active component of SIL, counteracted the estradiol 17-glucuronide-induced decrease in the percentage of couplets secreting apically the fluorescent bile acid analogue, cholyl-lysyl-fluorescein. These results show that SIL protects against EE-induced cholestasis by normalizing mainly the decrease in the bile salt pool size and HCO3 output, and probably by counteracting the cholestatic effect of its cholestatic, glucuronidated metabolite.
