Nonresponsiveness of the rat liver to alkylating carcinogens given by gavage.

Carcinogenic alkylating agents administered orally are metabolized in the liver and alkylate DNA in liver cells of rats and hamsters. They frequently, but not always, induce liver tumors, in addition to tumors of other organs. Directly acting alkylating agents, such as alkylnitrosoureas and alkylnitrosocarbamates, rarely induce liver tumors, although they alkylate DNA in liver cells. The methylating agents nitrosodimethylamine and azoxymethane induce high incidences of liver tumors in rats when given in drinking water, but few or no liver tumors when given by gavage, although the total dose and the weekly dose were the same in either regimen. In contrast, methylnitrosoethylamine and nitrosodiethylamine give rise to liver tumors in rats in high incidences whether given by gavage or in drinking water. Sharp differences are also observed with other nitrosamines, such as those containing a propyl group with an oxygen substituent in the 2-position. These discrepancies indicate that, in addition to alkylation of DNA, pharmacokinetics of dosing and distribution and other reactions of the carcinogen are the dominant factors in determining the development of tumors in the liver.