H. Gutmann, S. B. Galitski, W. A. Foley
Feb 1, 1968
Citations
1
Influential Citations
6
Citations
Quality indicators
Journal
Cancer research
Abstract
In order to test the idea that the lack of carcinogenicity of the o -amidofluorenols, N -(1-hydroxy-2-fluorenyl)acetamide and N -(3-hydroxy-2-fluorenyl)acetamide, is due to the hydrophilic phenolic hydroxyl group, the methylated derivatives, N -(1-methoxy-2-fluorenyl) acetamide and N -(3-methoxy-2-fluorenyl)acetamide as well as the hydrochlorides of 1-methoxy-2-fluorenamine and 3-methoxy-2-fluorenamine, were prepared, and their carcinogenicity was evaluated in the rat. N -(1-Methoxy-2-fluorenyl)acetamide and 1-methoxy-2-fluorenamine hydrochloride, when administered orally to male rats for 5 months, gave a tumor incidence of 27 and 50%, respectively. Approximately one-half of the lesions produced by either compound were adenocarcinomas of the small intestine. N -(3-Methoxy-2-fluorenyl)acetamide and 3-methoxy-2-fluorenamine hydrochloride were inactive. The low-to-moderate carcinogenicity of N -(1-methoxy-2-fluorenyl)acetamide and of 1-methoxy-2-fluorenamine hydrochloride contrasted sharply with the high carcinogenicity of the isomeric N -(7-methoxy-2-fluorenyl)acetamide and of N -2-fluorenyl acetamide, which were run for comparison under identical conditions. N -(7-Methoxy-2-fluorenyl) acetamide appeared to be specifically active toward the mammary gland. The intracellular removal of the O -methyl group of N -(1-methoxy-2-fluorenyl)acetamide was demonstrated by means of N -(1-methoxy-2-fluorenyl)acetamide labeled with 14C in the methyl group. The formation of N -(1-hydroxy-2-fluorenyl)acetamide, indicated by the radioactive tracer experiments, was confirmed by the isolation of N -(1-hydroxy-2-fluorenyl)acetamide from the urine of rats dosed with N -(1-methoxy-2-fluorenyl)acetamide. The metabolic O -demethylation of N -(1-methoxy-2-fluorenyl)acetamide was compatible with the view that N -(1-hydroxy-2-fluorenyl)acetamide, when liberated in situ , may be weakly carcinogenic. However, the striking differences in the carcinogenicities, as well as in the sites of action of the o -methoxy compounds and of N -2-fluorenyl acetamide, make it exceedingly improbable that the carcinogenic activity of N -2-fluorenylacetamide is mediated through N -(1-hydroxy-2-fluorenyl)acetamide or through the o -quinone imine, 2-imino-1,2-fluorenoquinone, resulting from N -(1-hydroxy-2-fluorenyl)acetamide by the sequential reactions of deacetylation and oxidation.