Studies on the induction of cholangiofibrosis by coumarin in the rat.

The histogenesis of coumarin-induced cholangiofibrosis in the rat has been determined. Proliferation of ductal structures was preceded by extensive damage to hepatocytes in the centrilobular region. Focal proliferation of ducts and fibrous tissue was present at 3 months and typical areas of cholangiofibrosis at 6 months. By 18 months the lesion was extensive and contained areas showing bizarre histological features suggestive of malignancy although no evidence of extra-hepatic metastasis was found. The lesion in animals returned to standard diet showed varying degrees of involution with extensive atrophy and fibrosis. A number of parameters of hepatic mixed function oxidase activity were reduced during the initial treatment period, at later times there was recovery of some microsomal enzyme activities. The activity of gamma-glutamyltransferase and the hepatic content of non-protein sulphydryl groups, in contrast, were raised throughout the treatment period.