The relationship between microsomal enzyme induction and liver tumour formation : a study on the effects of xenobiotic and naturally occurring microsomal enzyme inducers on livers of male CF-1 mice

The effects of naturally occurring microsomal enzyme inducers on important hepatocellular pathways for the metabolism of foreign compounds (xenobiotics) and also upon the incidence of liver tumours in CF-1 mice treated or not with 10 mg dieldrin.kg ^-1diet were investigated using animals maintained on semi-synthetic diet and filter paper bedding as controls. The results of the study indicate that dieldrin administration to mice results in a generalized liver enlargement predominantly due to hyperplasia. Liver enlargement in dieldrin-treated mice was followed by the appearance of nodular liver tumours, first observed at the age of 43 weeks. Conventional rodent diet and sawdust bedding were shown to contain agents that induce the microsomal mono-oxygenase system of mouse liver. However, the extent of mono-oxygenase induction by these factors was less pronounced than that caused by dieldrin. In contrast to the effects of dieldrin, conventional diet and sawdust bedding did not cause any significant induction of secondary drug-metabolizing enzyme systems, e.g. epoxide hydratase, glutathione S-epoxide transferase and UDP-glucuronyl transferase. Histopathological examination of livers demonstrated a low incidence of tumours in the livers of mice not treated with dieldrin. These tumours were generally benign in character although a few showed morphological characteristics associated with malignant liver cell tumours. The overall incidence of liver tumours was significantly increased in dieldrin-treated animals. Both benign and malignant liver tumours were found in dieldrin-treated mice; the latter type of lesion showing evidence of lung metastasis. Conventional diet and sawdust bedding did not exert any obvious influence on the development of 'spontaneous' tumours in the livers of male CF-1 mice.It is concluded that microsomal enzyme inducers such as dieldrin act by facilitating the expression of a pre-existing oncogenic factor, probably by inducing hyperplasia.