Role of extent and persistence of DNA modifications in chemical carcinogenesis by aromatic amines.

The initial step in tumor formation with aromatic amines is assumed to involve the modification of nucleic acids. Reactive metabolites bind covalently to purine and pyrimidine bases. The extent of formation of DNA adducts and their persistence is therefore expected to correlate with the biological effect. Using [3H]trans-4-amino-stilbene derivatives as model compounds, several parameters have been measured in susceptible and nonsusceptible rat tissues: total initial DNA binding, initial pattern of adducts, persistence of DNA adducts, accumulation of DNA binding after repeated doses, and persistence of DNA adducts after repeated doses. They did not correlate with tissue susceptibility. The tissue burden decreased in the order: liver greater than kidney greater than lung greater than glandular stomach greater than Zymbal gland. The latter tissue is the primary target for tumor formation. Comparison with other aromatic amines shows that aminostilbene derivatives are no exceptions. The role of specific nucleic acid modifications for mutagenic and carcinogenic effects is also difficult to evaluate in these cases. It is therefore emphasized that modulation of secondary steps in the multistage process may largely influence the final outcome. The role of cell proliferation and its stimulation as well as tumor promoting effects are discussed. Aminostilbene derivatives appear to produce primary lesions quite efficiently in rat liver but lack cytotoxic and promoting properties for this tissue.