Mechanisms of silymarin (SIL)-mediated protection of 17 α-ethinylestradiol (EE)-induced cholestasis in the rat

CROCENZI, FERNANDO A.; SÁNCHEZ POZZI, ENRIQUE J; PELLEGRINO, JOSÉ M; ROMA, MARCELO G

Congreso; 50th Annual Meeting of the American Association for the Study of Liver Diseases; 1999

We have previously shown (Hepatology 28 (4, Pt. 2): 181A, 1998) that SIL partially prevented the decrease in bile flow (BF; µl/min/g liver wt) and fully prevented the decrease in bile salt output (BSO, nmol/min/g liver wt) and the increase in serum alkaline phosphatase induced by EE in Wistar rats. In this study, we evaluated the mechanisms involved in such a protective effect. EE (5 mg/kg b.w., s.c., daily, for 5 days) induced a significant decrease in the BS-independent fraction of the bile flow as evaluated by the y-intercept of the regression line between BF and BSO during infusion of tauroursodeoxycholate (TUDC). The size of the endogenous BS pool, assessed as the total amount of BS excreted after complete BS pool washout following a chronic bile drainage, as well as the maximum transport rate (Tm) of both TUDC and sulfobromophtalein (BSP), were also decreased by the cholestatic compound. Simultaneous administration of SIL (100 mg/kg b.w., i.p., daily, for 5 days) partially prevented these effects, whereas the flavonolignan per se only modified the size of the BS pool. These results show that SIL was instrumental in attenuating the impairment in both the BS-independent and the BS-dependent fractions of the BF induced by EE. At least two mechanisms seem to be involved in the normalization of the basal BSO induced by SIL, namely, the restoration of the BS pool size, a critical driving force for the BS output, and the amelioration of the rate-limiting step in the hepatic handling of BS, i.e. their canalicular transfer, as evaluated by the TUDC Tm. Bearing in mind that glutathione is a chief determinant of the BSIF and that this anion is thought to share with BSP their canalicular transport system, the improvement of the Tm value for BSP may help to explain the SIL-mediated improvement of the BSIF. Studies aimed to test this hypothesis are in progress.