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Nonresponsiveness of the rat liver to alkylating carcinogens given by gavage
1Laboratory of Chemical and Physical Carcinogenesis, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702.
Abstract:
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.
Insights
Oral exposure to carcinogenic alkylating agents can lead to liver tumors. However, the route of administration significantly impacts tumor development, suggesting pharmacokinetics are crucial for liver cancer risk.
Area of Science:
- Toxicology
- Hepatocarcinogenesis
- Chemical carcinogenesis
Background:
- Carcinogenic alkylating agents are metabolized in the liver, alkylating DNA in liver cells.
- These agents frequently induce tumors in various organs, including the liver, but not always.
- Directly acting alkylating agents rarely cause liver tumors despite DNA alkylation.
Purpose of the Study:
- To investigate the influence of administration route on liver tumor induction by oral alkylating agents.
- To understand the factors determining liver tumor development beyond DNA alkylation.
Main Methods:
- Comparison of liver tumor incidence in rats and hamsters administered different alkylating agents via drinking water versus gavage.
- Analysis of pharmacokinetic factors and other carcinogen reactions in relation to tumor formation.
Main Results:
- Methylating agents (nitrosodimethylamine, azoxymethane) induced high liver tumor incidences in rats via drinking water but not gavage, at equal doses.
- Other nitrosamines showed varied liver tumor induction depending on administration route.
- Directly acting agents showed low liver tumor incidence despite DNA alkylation.
Conclusions:
- The route of administration and pharmacokinetics of dosing and distribution are critical determinants of liver tumor development.
- DNA alkylation alone is insufficient to predict liver carcinogenicity; other factors significantly influence outcomes.