Phenobarbital and other Liver Tumor Promoters
All liver tumor promoters mentioned above stimulate growth of normal liver. The growth response is due to cellular hypertrophy and/or increased rate of DNA (and cell) replication and/or decreased rate of cell death. Some important aspects pertinent to the control of liver growth are reviewed.
Hepatocytes in foci or islands of altered cells (putatively preneoplastic = pn) show higher rates of replication than normal liver cells; various different liver tumor promoters cause a further increase of proliferation of focal cells. The increased proliferative activity is found in different island phenotypes and thus seems to be a useful marker of the putative preneoplastic state. Moreover, the enhanced proliferation of pn cells in response to promoters may provide the basis for developing a short-term test on promotional activity. The focal cells respond to several factors limiting proliferation in normal liver suggesting that they are not autonomous with respect to growth control.
Early pn foci grow slowly without promotion despite of the relatively high rates of cell replication. Thus their cells seem to have a much shorter life-time than normal hepatocytes, or to undergo reversion to the normal phenotype (“remodelling”). Promoters seem to accelerate island enlargement by increasing cell replication and delaying cell death or remodelling. Thus, tumor promoters enhance the manifestation of the proliferative advantage of the putative initiated cell population.
In addition promoters caused increases in the n u m b e r of detectable islands. This can partially be explained by enlargement of existing islands, but phenotypic changes that would enhance the probability of detection of “remodelling” islands, and growth of dormant initiated cells probably contribute to the apparent increase of island number.
Putative pn foci of unknown (“spontaneous”) origin are frequent in the liver of aged Wistar rats. They are morphologically and functionally (increased proliferation) very similar to those induced by carcinogens and are responsive to the mitogenic effect of tumor promoters. Promotion of these “spontaneous” foci may explain tumor appearance after long-term application of promoters alone. These findings imply that the longterm carcinogenicity bioassay as currently performed does not discriminate between initiating and promoting properties of a test compound if the animals used develop spontaneous preneoplastic lesions in the organ affected.
KeywordsEstrogen Progesterone NADPH Estradiol Cyclohexane
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