Synthesis and excretion profile of 1,4-[14C]phenylenebis(methylene)selenocyanate in the rat


1To whom correspondence should be addressed 1,4-Phenylenebis(methylene)selenocyanate (p-XSC) inhibits chemically induced tumors in several laboratory animal models. To understand its mode of action, we synthesized p-[14C]XSC, examined its excretion pattern in female CD rats and also the nature of its metabolites. p-[14C]XSC was synthesized from a,a-dibromo-p-[ring-14C]xylene in 80% yield. The excretion profile of p-[14C]XSC (15.8 mg/kg body wt, 200 mCi/rat, oral administration, in 1 ml corn oil) in vivo was monitored by measuring radioactivity and selenium content. On the basis of radioactivity, ~20 % of the dose was excreted in the urine and 68 % in the feces over 3 days. The cumulative percentages of the dose excreted over 7 days were 24 % in urine and 75 % in feces, similar to excretion rates of selenium. According to selenium measurement, <1 % of the dose was detected in exhaled air; radioactivity was not detected. Only 15 % of the dose was extractable from the feces with EtOAc and was identified as tetraselenocyclo-phane (TSC). Most of the radioactivity remained tightly bound to the feces. Approximately 10 % of this bound material converted to TSC on reduction with NaBH4. Organic soluble metabolites in urine did not exceed 2 % of the dose; sulfate (9 % of urinary metabolites) and glucuronic acid (19.5 % of urinary metabolites) conjugates were observed but their structural identification is still underway. Co-chromatography with a synthetic standard led to the detection of terephthalic acid (1,4-benzenedicarboxylic acid) as a minor metabolite. The major urinary conjugates con-tained selenium. Despite the low levels of selenium in the exhaled air, the reductive metabolism of p-XSC to H2Se cannot be ruled out. Identification of TSC in vivo indicates that a selenol may be a key intermediate responsible for the chemopreventive action of p-XSC

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