An experimental model of hepatic fibrosis induced by the administration of dibutyltin dichloride.

Dibutyltin dichloride (DBT) was investigated for its ability to induce hepatic fibrosis in rats. Since hydroxyproline does not appear in significant amounts in noncollagen protein and prolyl residues in collagen are not hydroxylated before they are in peptide-bound form, the conversion of isotopically labeled proline to hydroxyproline by prolyl hydroxylase was taken as one parameter reflecting the rate of collagen formation. In vitro collagen synthesis was determined by incubation of liver biopsies with labeled proline, after which incorporation of label into collagenase-digestible protein was compared to incorporation into collagenase-resistant protein. Hydroxyproline content served as a parameter of collagen accumulation. DBT, administered by oral intubation (10 and 20 mg/kg) daily for 4 days, produced inflammation in portal tracts and biliary damage at the end of this period. Prolyl hydroxylase activity was increased over control values in both treated groups, and in vitro collagen synthesis was increased in the higher dose group. DBT, administered by oral intubation (10 and 20 mg/kg) every other day for 12 days, produced extensive inflammation in portal tracts, biliary damage, fibrosis, necrosis, infarcted areas, and granulomatous lesions. In the higher dose group increases in hydroxyproline content, prolyl hydroxylase activity, and relative collagen synthesis in vitro were observed at the end of the 12-day period. DBT did not increase prolyl hydroxylase activity of L929 cells when added to culture media for 24 hr. These results suggest that DBT-induced fibrogenesis is a result of biliary damage and/or inflammatory processes rather than direct stimulation of fibroblasts.