Proto-oncogene activation during chemically induced hepatocarcinogenesis in rodents

The liver is a frequent site for the development of chemically induced cancer in rodents. This is primarily owing to the capability of the liver to activate a large variety of exogenous chemicals metabolically to reactive electrophilic species that can covalently interact with cellular DNA and other macromolecules (Miller and Miller, 1966; Miller, 1978). It is the potential alteration of the hepatocellular genome by mutational events that forms the theoretical basis for the heritable nature of cancer as well as, at least in part, the altered phenotype of neoplastic cells; however, our understanding of the exact nature of these heritable genetic alterations remains fragmentary. Within the last decade the delineation of the molecular basis of viral oncogenesis, especially by retroviruses, has revealed potential targets in the cell genome for the reactive forms of chemical agents in relation to their carcinogenic action (Bishop, 1987). Primary among such potential targets are proto-oncogenes, homologous to the transforming genes of oncogenic retroviruses from which they have evolved (Temin, 1974). The objective of this brief review is to consider the evidence that induced alterations in the structure and/or regulation of expression of proto-oncogenes may play one or more roles in rodent hepatocarcinogenesis, especially in relation to the stages of initiation, promotion, and progression (Pitot et al., 1988).