Beneficial effects of silymarin on estrogen-induced cholestasis in the rat: A study in vivo and in isolated hepatocyte couplets

Citation
Fa. Crocenzi et al., Beneficial effects of silymarin on estrogen-induced cholestasis in the rat: A study in vivo and in isolated hepatocyte couplets, HEPATOLOGY, 34(2), 2001, pp. 329-339
Citations number
66
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Gastroenerology and Hepatology","da verificare
Journal title
HEPATOLOGY
ISSN journal
0270-9139 → ACNP
Volume
34
Issue
2
Year of publication
2001
Pages
329 - 339
Database
ISI
SICI code
0270-9139(200108)34:2<329:BEOSOE>2.0.ZU;2-D
Abstract
The effect of silymarin (SIL) on 17 alpha -ethynylestradiol (EE)-induced ch olestasis 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 in duced 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 b oth 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 c ytochrome P450 isoenzyme involved in the oxidative metabolism of EE, and ha d no inhibitory effect on the UDP-glucuronosyltrasferase isoforms involved in the formation of its 17 beta -glucuronidated, more cholestatic metabolit e. Pretreatment of isolated rat hepatocyte couplets with silibinin, the maj or, active component of SIL, counteracted the estradiol 17 beta -glucuronid e-induced decrease in the percentage of couplets secreting apically the flu orescent bile acid analogue, cholyl-lysyl-fluorescein. These results show t hat SIL protects against EE-induced cholestasis by normalizing mainly the d ecrease in the bile salt pool size and HCO3- output, and probably by counte racting the cholestatic effect of its cholestatic, glucuronidated metabolit e.