The Carcinogenic Action and Metabolism of Urethan and N-Hydroxyurethan

Abstract

This chapter discusses the carcinogenic actions of urethane for several types of tumor, including lung adenomas, skin papillomas, malignant lymphomas, hepatomas, liver hemangiomas, mammary carcinomas, and other tumors in mice and other species. It emphasizes on the possible mechanisms of action of urethan and examines the chemical specificity for some of the varied actions of urethane. Urethan is structurally one of the simplest carcinogens; it is soluble in both water and lipids and was the first water-soluble carcinogen to be discovered. Certain metabolic effects of urethan, and the metabolism of urethan itself, are discussed in the chapter in relation to its carcinogenic action. The biological effects of urethan depend on the direct inhibition of nucleic acid synthesis, especially of the pyrimidine bases, and an apparent antagonism between urethan and the pyrimidines does exist. Thus, the in vivo chromosome-damaging and anti-cancer actions of urethan were antagonized by thymine, thymidine, glutamine, and (for anticancer action) cytidine, 5-methylcytosine, asparagine, and aspartic acid. Urethan may be determined in body fluids by alkaline hydrolysis and the measurement of the liberated ethanol. Recently, it was proposed that urethan might act after metabolic conversion into N-hydroxyurethan (NHU). The available evidence indicates that the supposed active metabolite of urethane is not NHU, which conversely seems to act as carcinogen after conversion into urethan. NHU is a hydroxamate and an ethyl ester, which may be synthesized by the reaction of hydroxylamine with ethyl chloroformate. NHU shows some interesting cytotoxic and anticancer actions more strongly than urethan and specifically kills cells in the DNA-synthesizing S phase. These effects appear to depend on a suppression of DNA synthesis, or possibly on known chemical reactions of NHU with DNA.