Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats.
Silymarin (SIL), a standardized plant extract containing about 60% polyphenole silibinin, is used as a hepatoprotective agent. Its antifibrotic potential in chronic liver diseases has not been explored. Therefore, we applied SIL to adult Wistar rats that were subjected to complete bile duct occlusion (BDO) by injection of sodium amidotrizoate (Ethibloc). This treatment induces progressive portal fibrosis without significant inflammation. Rats with sham-operation that received SIL at 50 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/kg/d during weeks 1 through 6 or doses of 50 mg/kg/d during weeks 4 through 6 of BDO. Animals were sacrificed after 6 weeks for determination of blood chemistries, total and relative liver collagen (as hydroxyproline [HYP]), and the serum aminoterminal propeptide of procollagen type III (PIIINP). BDO in untreated rats caused an almost ninefold increase 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 25 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 antifibrotic agent. The single value of PIIINP at killing paralleled the antifibrotic activity of SIL with 11.6 +/- 3.8 and 9.9 +/- 3.7 vs. 15.3 +/- 5.2 microg/L in both high-dose groups (P < .05 and P < .01, respectively, vs. rats with BDO alone). Except for a decreased alkaline phosphatase and a lower histological fibrosis score in the groups that received SIL, clinical-chemical parameters were not different among all groups with BDO. We therefore conclude that 1) BDO with Ethibloc is a suitable model to test for pure antifibrotic drugs because it induces progressive rat secondary biliary fibrosis without major inflammation; 2) oral SIL can ameliorate hepatic collagen accumulation even in advanced (biliary) fibrosis; and 3) PIIINP appears to be a suitable serum marker to monitor the inhibition of hepatic fibrogenesis in this model of biliary fibrosis.
Boigk
G
G
Department of Gastroenterology and Hepatology, Klinikum Benjamin Franklin, Free University of Berlin, Germany.
Stroedter
L
L
Herbst
H
H
Waldschmidt
J
J
Riecken
E O
EO
Schuppan
D
D
D000818:Animals; D001652:Bile Ducts / Q000502:physiology*; D015415:Biomarkers / Q000097:blood; D001835:Body Weight; D003094:Collagen / Q000187:drug effects / Q000378:metabolism*; D003973:Diatrizoate / Q000633:toxicity; D005260:Female; D005355:Fibrosis; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008111:Liver Function Tests; D009336:Necrosis; D009929:Organ Size; D010446:Peptide Fragments / Q000097:blood; D011347:Procollagen / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D012838:Silymarin / Q000494:pharmacology*
D015415:Biomarkers; D010446:Peptide Fragments; D011347:Procollagen; D012838:Silymarin; C041876:procollagen Type III-N-terminal peptide; D003973:Diatrizoate; D003094:Collagen