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Differences in the Metabolism of N-2-Fluorenylacetamide in the Guinea Pig and the Rat^*

John H. Weisburger, Elizabeth K. Weisburger and Harold P. Morris

( Laboratory of Biochemistry, National Cancer Institute,^, Bethesda 14, Md.)

N-2-Fluorenylacetamide, a potent carcinogen in rats and some other species, appears to be noncarcinogenic in guinea pigs. The possibility of a difference in metabolism of the compound in rats and guinea pigs was investigated by means of C¹⁴-and N¹⁵-labeled N-2-fluorenylacetamide, to apprehend the possible causes for this species-connected divergence.

After a single oral dose of the labeled chemical, the isotope was excreted rapidly by guinea pigs, and tissue levels were low. After 4–5 days about 80–90 per cent of a dose appeared in the urine and 10–20 per cent in the feces. The major portion was eliminated during the 1st day. Ether extractions and enzymic hydrolysis experiments of the urinary metabolites indicated that 1–2 per cent were unconjugated, ether-extractable compounds, 70–90 per cent were glucuronic acid, and 1–2 per cent sulfuric acid conjugates.

Paper and column chromatographic technics showed that N-(7-hydroxy-2-fluorenyl)acetamide was the principal urinary metabolite, amounting to about 70 per cent of a dose of N-2-fluorenylacetamide. In addition, small amounts of the 8- and 5-hydroxylated derivatives, and only traces of the 1- and 3-hydroxylated compounds, were excreted in the urine. In contrast, rats produced considerably higher levels of these compounds, with a corresponding decrease in the 7-hydroxylated material. These species differences suggest the likelihood that there are several different enzymes hydroxylating aromatic rings.

Carcinogenesis by N-2-fluorenylacetamide is discussed in terms of a possible involvement of the ortho-aminohydroxy derivatives produced by the metabolic transformation of the compound.

^* Presented in part before the Division of Biological Chemistry at the 131st meeting of the American Chemical Society, Miami, Fla., April, 1957; Abstracts of Papers, p. 10-C.

With the able technical assistance of Mr. P. H. Grantham and Mrs. A. R. Parker.

National Institutes of Health, Public Health Service, U.S. Department of Health, Education, and Welfare.

Received 4/ 9/58.