Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha 1(I) and TIMP-1

Background/Aims: Silymarin reduces hepatic collagen accumulation by 35% in rats with secondary biliary cirrhosis. The aim of the present study was to explore its antifibrotic mechanism. Methods: Thirty female adult Wistar rats were allocated to (1) bile duct oc clusion, (2) bile duct occlusion and oral silymarin at 50 mg/kg per day, an d (3) sham operation and oral silymarin at 50 mg/kg per day. Steady-state m RNA levels for procollagen alpha1(I), tissue inhibitor of metalloproteinase s-1 (TIMP-1), and transforming growth factor (TGF) beta1 were determined by multi-probe ribonuclease protection assay. Results: After 6 weeks of bile duct occlusion, liver collagen content was i ncreased 12-fold, when compared with the sham-operated controls. These anim als displayed 17-, 6.5- and 16-fold higher transcript levels for procollage n alpha1(I), TIMP-1 and TGF beta1 (P < 0.01). Silymarin downregulated eleva ted procollagen alpha1(I), TIMP-1 and TGF beta1 mRNA levels by 40-60% (P < 0.01). These lowered hepatic profibrogenic transcript levels correlated wit h decreased serum levels of the aminoterminal propeptide of procollagen typ e III. Conclusions: Silymarin suppresses expression of profibrogenic procollagen a lpha1(I) and TIMP-1 most likely via downregulation of TGF beta1 mRNA in rat s with biliary fibrosis. The serum procollagen type III propeptide level mi rrors profibrogenic mRNA expression in the liver. (C) 2001 European Associa tion for the Study of the Liver. Published by Elsevier Science B.V. All rig hts reserved.