Silymarin (SIL) protects against estrogen-induced cholestasis in the rat

CROCENZI, FERNANDO A.; SÁNCHEZ POZZI, ENRIQUE J; CATANIA, VIVIANA A.; LUQUITA, MARCELO G.; FAVRE, CRISTIÁN O.; PELLEGRINO, JOSÉ M.; MOTTINO, ALDO D; ROMA, MARCELO G; COLEMAN, ROGER

Congreso; Biennial Scientific Meeting of the International Association for the Study of the Liver (IASL); 1998

The effect of the hepatoprotective agent SIL on estrogen-induced cholestasis was evaluated in Wistar rats. 17α-ethinylestradiol (EE, 5 mg/kg b.w., s.c., daily, for 5 days) induced a significant decrease in bile flow, bile salt output and cumulative bromosulfophtalein (BSP) output, as well as an increase in serum alkaline phosphatase (AP) activity and in the proportion of total (glyco- + tauro-) muricholate relative to total cholate (MC/C) in bile. These effects were total or partially counteracted by the simultaneous administration of silymarin (100 mg/kg b.w., i.p.). Compartmental analysis of BSP plasma decay revealed that SIL significantly improved the decrease in the canalicular excretion fractional transfer rate induced by EE (from 0.026±0.005 to 0.094±0.018, p<0.01). SIL decreased rather than increased CYP3A4, the cytochrome P450 isoenzyme involved in the catabolism of EE, and had no effect on EE UDP-glucuronosyltransferase, the enzyme that converts EE in its glucuronized, more cholestatic parent compound. These results suggest that SIL counteracts the harmful effects of EE at a post-metabolic level. This contention was supported further by experiments in which isolated rat hepatocyte couplets pre-treated with silibinin, the major, active component of silymarin, were exposed to the glucuronized EE analogue estradiol 17ß-glucuronide (17ß-EG). Silibinin (2.5 µM, 30 min) fully counteracted the decrease in the percentage of couplets accumulating the fluorescent bile acid analogue cholyl-lysyl-fluorescein in their canalicular vacuoles up to a concentration of 17ß-EG of 20 µM, and partially at least up to a concentration of 17ß-EG of 50 µM. These results show that SIL protects against EE-induced cholestasis, probably by interfering with the cholestatic effect of its glucuronized parent compound.