Hepatocarcinogenesis by Non-Genotoxic Compounds
Many compounds have been found to produce liver tumors after long-term treatment of experimental animals, mostly rodents, without exhibiting detectable genotoxic activity or potential. These agents include phenobarbital, certain estrogens and progestins, hypolipidemic and other drugs as well as environmental pollutants such as DDT, hexachlorocyclohexane, phthalate plasticizers etc. After short-term treatment the agents induce liver growth and increases of certain enzymes which probably represents enhanced expression of specific gene programs. Mechanisms involved include stimulation of cell proliferation and inhibition of cell death (apoptosis).
In addition to negative tests for genotoxicity these agents generally are also negative when assayed for tumor initiating activity in the liver; however, many but not all compounds show tumor promoting activity. Tumor promotion may be due to overexpression of gene programs in initiated/preneoplastic cells in the liver; inhibition of death of preneoplastic cells by promoters seems to cause rapid growth of preneoplastic lesions. Possible implications for risk assessment are discussed.
KeywordsTumor Promoter Peroxisome Proliferators Cyproterone Acetate Liver Growth Preneoplastic Cell
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