Chemically induced cell proliferation in liver carcinogenesis.

Hepatocyte proliferation has been noted in several stages of the hepatocarcinogenic process. Immediately associated with DNA adducts, hepatocyte proliferation clearly has been shown to enhance initiation. The evidence is strong that enhanced cell proliferation, preceeding DNA repair of endogenous and exogenous lesions, thereby results in the fixation of mutagenic events. In contrast to the rather well-established role of hepatocyte proliferation in the initiation phase of carcinogenesis, the role of chemically induced hepatocyte proliferation in liver tumor development is supported by sparse information. Although the available data suggest that chronic cell proliferation in the liver may be associated with tumorigenesis, this information is limited to simple correlations and a relatively small number of chemicals. In the carcinogenic process, another aspect of chemically induced cell proliferation would be direct stimulation of the altered hepatocytes to proliferate and develop tumors rapidly. This latter hypothesized activity is the least well characterized and documented for cell proliferation at this time. Because a quantitative relationship between hepatocyte proliferation and carcinogenic potential has been established for only a few chemicals, general conclusions must await data from correlative studies with other chemicals. Some correlations have been noted, but correlations do not prove cause and effect. The underlying mechanisms of chemically induced cell proliferation must be understood before cause-and-effect relationships between hepatocyte proliferation and enhancement of multiple stages of liver tumor development can be drawn.