Preventive effect of silymarin against taurolithocholate-induced cholestasis in the rat.

CROCENZI, FERNANDO A; ENRIQUE JUAN SANCHEZ POZZI; M PELLEGRINO, JOSÉ; RODRÍGUEZ GARAY, EMILIO A; MOTTINO, ALDO D; G ROMA, MARCELO

BIOCHEMICAL PHARMACOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2003 vol. 66 p. 355 - 364

0006-2952

Increased amounts of monohydroxylated bile salts (BS) have been found in neonatal cholestasis, parenteral nutrition-induced cholestasis and Byler?s disease, among others.We analyzed whether the hepatoprotector silymarin (SIL), administered i.p. at the dose of 100 mg/kg/day for 5 days, prevents the cholestatic effect induced by a single injection of the modelmonohydroxylated BS taurolithocholate (TLC, 30 mmol/kg, i.v.) in maleWistar rats. TLC, administered alone, reduced bile flow, total BS output, and biliary output of  glutathione and HCO3 during the peak of cholestasis (75, 67, 81, and 80%, respectively, P < 0:05). SIL prevented partially these alterations, so that the drops of these parameters induced byTLCwere of only41,25,60, and64%, respectively (P < 0:05 vs.TLCalone); these differences between control and SIL-treated animals were maintained throughout thewhole (120 min) experimental period. Pharmacokinetic studies showed that TLC decreased the intrinsic fractional constant rate for the canalicular transport of both sulfobromophthalein and the radioactive BS [14C]taurocholate by 60 and 68%, respectively (P < 0:05), and these decreases were fully and partially prevented by SIL, respectively. SIL increased the hepatic capability to clear out exogenously administered TLC by improving its own biliary excretion (þ104%, P < 0:01), and by accelerating the formation of its  non-cholestatic metabolite, tauromurideoxycholate (þ70%, P < 0:05).We conclude that SIL counteracts TLC-induced cholestasis by preventing the impairment in both the BS-dependent and -independent fractions of the bile flow. The possible mechanism/s involved in this beneficial effect will be discussed.