Distribution of Radioactivity and Metabolism of Formic Acid 2-[4-(5-Nitro-2-furyl)-2-14C-2-thiazoiyl]hydrazide following Oral Administration to Rats and Mice

Samuel M. Cohen, Arthur Alter, George T. Bryan

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Abstract

Formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl]hydrazide (FNT) has demonstrated carcinogenic activity in rats and mice, inducing high incidences of kidney and breast tumors in rats and forestomach tumors and lymphocytic leukemia in mice. Tumors of other organs were also induced in lower incidences. The excretion patterns in rats and mice were essentially similar when FNT was administered intragastrically, with a majority of the radioactivity excreted within 24 hr in the urine and less in the feces after 24 hr. Very little was expired as 14CO2and less than 2.5% of the radioactivity was left in the animal after 96 hr. The tissue distribution of the radioactivity in rats demonstrated the highest concentrations in the kidney and forestomach of the rat and mouse, respectively. Concentrations in the rat breast and mouse thymus and spleen were comparable to the levels in the carcass, while levels in other tissues were similar to or somewhat higher than those in the carcass. When the urine from these animals was chromatographed on Whatman No. 1 paper and developed with methanol:butanol:ben-zene: water: glacial acetic acid (40:20:20:20:1), the radioactivity with an RF corresponding to the original chemical was less than 10% (usually 2 to 5%) of the total activity in the urine. This suggested that the chemical was metabolized before being excreted in the urine. After administration of FNT intragastrically at 0, 4, and 8 hr to weanling female rats, the rats were killed at 12 hr and the kidneys and liver were fractionated by ultracentrifugation. Distribution of radioactivity in the nuclear, mitochondrial, microsomal, and cytosol fractions was 28.4, 14.6, 5.7, and 51.2% and 20.2, 8.0, 3.4, and 68.4% in liver and kidney, respectively. When the cytosol fraction was chromatographed on Sephadex G-25 columns, 51.4% of the radioactivity appeared in the macromolecular peak from kidney and 19.8% appeared from liver. Comparable amounts of cytosol radioactivity were precipitated by cold trichloroacetic acid. When the labeled chemical was added to “cold” homogenate, greater than 90% of the radioactivity appeared in the cytosol fraction of kidney and liver and none appeared in the macromolecular peak when chromatographed on Sephadex G-25 columns. These data suggest that FNT interacts with kidney and liver macromolecules and that it must be metabolized before the interaction can occur. The synthesis of FNT is described.

Original languageEnglish (US)
Pages (from-to)2802-2809
Number of pages8
JournalCancer Research
Volume33
Issue number11
Publication statusPublished - Nov 1973

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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