SILYMARIN RETARDS COLLAGEN ACCUMULATION IN EARLY AND ADVANCED BILIARYFIBROSIS SECONDARY TO COMPLETE BILE-DUCT OBLITERATION IN RATS

Silymarin (SIL), a standardized plant extract containing about 60% pol yphenole silibinin, is used as a hepatoprotective agent. Its antifibro tic potential in chronic liver diseases has not been explored, Therefo re, we applied SIL to adult Wistar rats that were subjected to complet e bile duct occlusion (BDO) by injection of sodium amidotrizoate (Ethi bloc). This treatment induces progressive portal fibrosis without sign ificant inflammation. Rats with sham-operation that received SIL at 40 mg/kg/d (n = 10) and rats with BDO alone (n = 20) served as controls, whereas groups of 20 animals were fed SIL at a dose of 25 and 50 mg/k g/d during weeks 1 through 6 or doses of 50 mg/kg/d during weeks 4 thr ough 6 of BDO. Animals were sacrificed after 6 weeks for determination of blood chemistries, total and relative liver collagen (as hydroxypr oline [HYP]), and the serum aminoterminal propeptide of procollagen ty pe III (PIIINP). BDO in untreated rats caused an almost ninefold incre ase in total liver collagen (16.1 +/- 3.1 vs, 1.8 +/- 0.4 mg HYP, P < .001). SIL at 50 mg/kg/d reduced total HYP by 30% to 35%, either when given from week 1 through 6 or from week 4 through 6 after BDO (10.6 /- 2.7 and 10.2 +/- 3.9 mg HYP, both P < .01 vs, BDO alone), whereas 2 5 mg/kg/d were ineffective. Because SIL at 50 mg/kg/d also reduced the collagen content per gram of liver tissue, it acted as a true antifib rotic agent. The single value of PIIINP at killing paralleled the anti fibrotic activity of SIL with 11.6 +/- 3.8 and 9.9 +/- 3.7 vs. 15.3 +/ - 5.2 mu g/L in both high-dose groups (P < .05 and P < .01, respective ly, vs. rats with BDO alone), Except for a decreased alkaline phosphat ase and a lower histological fibrosis score in the groups that receive d SIL, clinical-chemical parameters were not different among all group s with BDO. We therefore conclude that 1) BDO with Ethibloc is a suita ble model to test for pure antifibrotic drugs because it induces progr essive rat secondary biliary fibrosis without major inflammation; 2) o ral SIL can ameliorate hepatic collagen accumulation even in advanced (biliary) fibrosis; and 3) PIIINP appears to be a suitable serum marke r to monitor the inhibition of hepatic fibrogenesis in this model of b iliary fibrosis.