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

1,4-Phenylenebis(methylene)selenocyanate (p-XSC) inhibits chemicallyinduced tumors in several laboratory animal models. To understand its modeof action, we synthesized p-[14C]XSC, examined its excretion pattern infemale CD rats and also the nature of its metabolites. p- [14C]XSC wassynthesized from alpha,alpha-dibromo-p-[ring-14C]xylene in 80% yield. Theexcretion profile of p-[14C]XSC (15.8 mg/kg body wt, 200 microCi/rat, oraladministration, in 1 ml corn oil) in vivo was monitored by measuringradioactivity and selenium content. On the basis of radioactivity,approximately 20% of the dose was excreted in the urine and 68% in thefeces over 3 days. The cumulative percentages of the dose excreted over 7days were 24% in urine and 75% in feces, similar to excretion rates ofselenium. According to selenium measurement, <1% of the dose wasdetected in exhaled air; radioactivity was not detected. Only 15% of thedose was extractable from the feces with EtOAc and was identified astetraselenocyclophane (TSC). Most of the radioactivity remained tightlybound to the feces. Approximately 10% of this bound material converted toTSC on reduction with NaBH4. Organic soluble metabolites in urine did notexceed 2% of the dose; sulfate (9 % of urinary metabolites) and glucuronicacid (19.5% of urinary metabolites) conjugates were observed but theirstructural identification is still underway. Co-chromatography with asynthetic standard led to the detection of terephthalic acid (1,4-benzenedicarboxylic acid) as a minor metabolite. The major urinaryconjugates contained selenium. Despite the low levels of selenium in theexhaled 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 keyintermediate responsible for the chemopreventive action of p- XSC.