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
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.