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Metabolism of Continuously Fed ¹⁴C-Labeled N-Hydroxy-N-2-Fluorenylacetamide at Various Intervals: Effect of Pituitary Hormones

Biology Branch, National Cancer Institute, Bethesda, Maryland 20014

Additional studies were performed on the mechanism of the promotion of hepatoma induction by pituitary hormones from a transplantable pituitary tumor MtT/F4 during carcinogenesis with N-hydroxy-N-2-fluorenylacetamide. Male Fischer rats with or without implanted MtT were fed ¹⁴C-labeled carcinogen in the diet for 64 days. Serial autopsies were performed to determine the alteration of binding of carcinogen metabolites to receptors on a continuing basis.

The intake of carcinogen-containing diet and the urinary excretion of radioactivity were relatively constant for the first 30-day period. Afterward both increased in animals on carcinogen alone, and appreciably so in rats also bearing MtT.

The urinary metabolites in animals fed carcinogen alone consisted of small amounts of unconjugated compounds (7 to 13% of urinary ¹⁴C), progressively higher percentages (from 29 to 47%) of glucosiduronic acids, and relatively constant amounts of sulfuric acid esters (10 to 15%). In tumor-bearing animals similar amounts of these metabolites were present early in the experiment, but after 30 days they increased, mainly in the glucosiduronic acid fraction. The amount of N-hydroxy-N-2-fluorenylacetamide excreted as glucuronide varied from 14 to 28% in rats on carcinogen alone but in the presence of MtT increased up to 44% of the urinary radioactivity after the 30th day.

The amount of radioactivity bound to liver proteins rose rapidly, reaching a plateau from the 8th to the 32nd day, and then mounted to another plateau between the 48th and 64th days. In the presence of MtT, protein-bound radioactivity grew continuously from the first period measured (Day 16) and attained the same level as without MtT on Day 64.

The urinary radioactivity and the labeling of the liver, plasma, and red cell proteins declined rapidly and at the same rate in animals with and without MtT during the last week in which the rats were on control diet.

¹ Visiting Scientist, NIH, on leave of absence from the Institute of Physical and Chemical Research, Tokyo, Japan.

Received 9/ 1/66. Accepted 12/23/66.