DIETHYLNITROSAMINE-INDUCED HEPATOCARCINOGENESIS IN RATS - A THEORETICAL-STUDY

Multiple data sets on hepatocarcinogenesis in rats resulting from pulse (single) or continuous exposure to diethylnitrosamine (DEN) are analyzed within the framework of a two-mutation carcinogenesis model in order to identify the underlying biological processes that control the pharmacodynamics of DEN-induced liver cancer. Our findings indicate: (1) Predictions of the two-mutation oncogenic model are consistent with empirical data on DEN-induced hepatocarcinogenesis. (2) The probability of the first genetic alteration (initiation) is linearly dependent on applied dose and decays exponentially following a pulse (single) dose or cessation of exposure. (3) The probability of initiation is proportional to the number of O4-ethyldeoxythymidine DNA adducts resulting from DEN exposure, indicating that these adducts are the likely promutagenic lesions in DEN-induced hepatocarcinogenesis. (4) The mitotic rates of initiated and transformed cells are nonlinear with dose. (5) The average growth rate of initiated hepatocytes as a function of DEN dose is related to Druckery's slope. (6) The probability of the second genetic event (transformation) is independent of applied dose, suggesting that it is the result of a spontaneous genetic alteration. © 1991.