Abstract
Prolonged administration to mice of nongenotoxic mixed-function oxidase (MFO) inducers, typified by the much-studied prototype phenobarbital (11), produces liver growth characterized by an increase in weight and centrilobular hepatocyte hypertrophy and hyperplasia. The cells have abundant eosinophilic cytoplasm due to proliferation of smooth endoplasmic reticulum and enlarged, irregular nuclei. When these nodular structures grow to compress the surrounding hepatocytes and lose their normal lobular architecture, they are, by consensus, adenomas. An increase in the incidence of only these tumors may be seen at the end of long-term studies with MFO inducers. According to Butler (1), the incidences of basophilic adenomas and invasive and metastatic carcinomas are not increased by MFO inducers. He provides evidence that these eosinophilic adenomas are different from those that occur spontaneously or those that are induced by genotoxic carcinogens in mice. They differ histologically, biochemically, in cell culture, and after transplantation into nude mice and usually do not have H-ras mutations on codon 61. They almost never develop into carcinomas that invade and metastasize, yet carcinomas (nodules within nodules) are found in some of these eosinophilic nodules (5). Thus, centrilobular hypertrophy and hyperplasia, a zonal adaptive response pattern (6), may provide a favorable environment for some autonomous growth. There appear to be several mechanisms by which this occurs. Phenobarbital, a nongenotoxic carcinogen (10), induced dose- and time-dependent liver enlargement in C57BL/IOJ mice during a 13-wk study. Although replication of centrilobular hepatocytes occurred only during the first week of study (8), persistent increases of mitogenic growth factors [transforming growth factor a (TGF-a) and hepatocyte growth factor (HGF)] and their receptors (epidermal growth factor receptor and HGF receptor) and decreases in the inhibitor of hepatocyte replication (TGF-131) and its receptor (mannose-6
Published Version
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