AN EXPERIMENTAL MODEL OF HEPATIC FIBROSIS INDUCED BY THE ADMINISTRATION OF DIBUTYLTIN DICHLORIDE

Abstract

Dibutyltin dichloride (DBT}, one of a series of dialkyltin derivatives used industrially as polyvinylchloride stabilizers and urethane catalysts, was investigated for its ability to induce liver fibrosis in rats. Collagen, the predominant protein in fibrotic tissue, is synthesized in a series of sequential steps consisting of assembly of a proline-rich and lysine-rich polypeptide precursor of collagen, enzymatic hydroxylation of some of the prolyl and lysyl residues, and glycosylation of some of · the hydroxylysyl residues. Since prolyl residues 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 is compared to incorporation into collagenase- resistant protein. Hydroxyproline content served as a parameter of increased collagen accumulation, since hydroxyproline does not appear in significant amounts in noncollagen protein. DBT was administered by oral intubation (10 and 20 mg/kg) every other day for 12 days. Histopathological observation in these rats revealed extensive inflammation in portal tracts, bile duct inflammation and proliferation, fibrosis, necrosis, infarcted areas and granulomatous lesions. In the higher dose group, a greater than two-fold increase in hydroxyproline content, a greater than 50% increase in prolyl hydroxylase activity and a two-fold increase in relative collagen synthesis in vitro was observed at the end of the 12 day period. DBT, administered by oral intubation (10 and 2·0 mg/kg) daily for four days, produced inflammation of portal tracts and bile duct inflammation and proliferation. Prolyl hydroxylase was increased 50 and 130% over control values in the · 10 and 20 mg/kg groups, respectively. In vitro collagen synthesis increased approximately five-fold in the higher dose group. However, there was no increase in relative collagen synthesis due to a concomitant elevation in noncollagen protein, probably as a result of inflammatory cell protein synthesis. DBT (3 x 10-7 and 3 x l0-6 M) had no effect on prolyl hydroxylase activity of 1929 mouse fibroblasts in cell culture.