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

Hepatology. 2001 Aug;34(2):329-39. doi: 10.1053/jhep.2001.26520.

Abstract

The effect of silymarin (SIL) on 17alpha-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 HCO(3)(-) 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 17beta-glucuronidated, more cholestatic metabolite. Pretreatment of isolated rat hepatocyte couplets with silibinin, the major, active component of SIL, counteracted the estradiol 17beta-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 HCO(3)(-) output, and probably by counteracting the cholestatic effect of its cholestatic, glucuronidated metabolite.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Alkaline Phosphatase / blood
  • Animals
  • Bile / drug effects
  • Bile / physiology
  • Bile Acids and Salts / antagonists & inhibitors
  • Bile Acids and Salts / metabolism
  • Cell Membrane / drug effects
  • Cholestasis / chemically induced*
  • Cholestasis / prevention & control*
  • Elasticity
  • Estradiol Congeners* / pharmacology
  • Ethinyl Estradiol* / pharmacology
  • Hepatocytes / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Membrane Transport Proteins*
  • Multidrug Resistance-Associated Proteins*
  • Rats
  • Rats, Wistar
  • Silymarin / pharmacology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Bile Acids and Salts
  • Estradiol Congeners
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Silymarin
  • Ethinyl Estradiol
  • multidrug resistance-associated protein 2
  • Alkaline Phosphatase
  • multidrug resistance-associated protein 1