David M. Conning

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.

Sustained induction of hepatic xenobiotic metabolising enzyme activities by phenobarbitone in C3H/He mice: Relevance to nodule formation

Phenobarbitone (PB) was administered to male C3H/He mice at a dose of 85 mg/kg/day in a semisynthetic diet for up to 90 weeks. Throughout the treatment period a sustained induction of a number of parameters of hepatic Phase I and Phase II xenobiotic metabolism was observed. Histological examination revealed hypertrophy of the centrilobular cells of the liver lobule in PB treated mice and after 25 weeks small basophilic nodules were found in control and PB treated animals. In addition eosinophilic nodules, which were often large, developed in PB treated mice. Xenobiotic metabolising enzyme activities in large excised nodules after 70 or 90 weeks of PB treatment were either similar to or greater than those present in surrounding host tissue. Both phenobarbitone- and polycyclic hydrocarbon-type mixed function oxidase enzyme activities were induced in large nodules. In conclusion, PB produced a sustained induction of xenobiotic metabolising enzymes both in host tissue and in large eosinophilic nodules. The formation of these nodules in C3H/He mice was thus not associated with any failure of induction of hepatic xenobiotic metabolism.