Preventive effect of silymarin against taurolithocholate-induced cholestasis in the rat.
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 100mg/kg/day for 5 days, prevents the cholestatic effect induced by a single injection of the model monohydroxylated BS taurolithocholate (TLC, 30 micromol/kg, i.v.) in male Wistar rats. TLC, administered alone, reduced bile flow, total BS output, and biliary output of glutathione and HCO(3)(-) 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 by TLC were of only -41, -25, -60, and -64%, respectively (P<0.05 vs. TLC alone); these differences between control and SIL-treated animals were maintained throughout the whole (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 (+104%, P<0.01), and by accelerating the formation of its non-cholestatic metabolite, tauromurideoxycholate (+70%, 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.
Crocenzi
Fernando A
FA
Instituto de Fisiología Experimental-Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET-U.N.R.), Suipacha 570, S2002LRL, Rosario, Argentina.
Sánchez Pozzi
Enrique J
EJ
Pellegrino
José M
JM
Rodríguez Garay
Emilio A
EA
Mottino
Aldo D
AD
Roma
Marcelo G
MG
D000818:Animals; D001646:Bile / Q000187:drug effects* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002255:Carbonic Acid / Q000378:metabolism; D002756:Cholagogues and Choleretics; D002779:Cholestasis / Q000139:chemically induced / Q000517:prevention & control*; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D008297:Male; D020011:Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012838:Silymarin / Q000627:therapeutic use*; D013658:Taurolithocholic Acid
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D020011:Protective Agents; D012838:Silymarin; D002255:Carbonic Acid; D013658:Taurolithocholic Acid; D005978:Glutathione