Disposition of [¹⁴C]furan in the male F344 rat

Abstract

In a recently completed 2‐yr bioassay, furan was found to induce cholangiocarcinomas at high incidence in rats. The disposition of single and multiple gavage doses of [2,5‐¹⁴C]furan has been determined in male F344 rats to aid in interpretation of that study. In the 24 h after dosing about 80% of the furan‐derived radioactivity was eliminated, primarily via urine and expired air. [¹⁴C]Carbon dioxide was a major metabolite, indicating that furan ring opening followed by complete oxidation of at least one of the labeled carbons was a major part of the overall metabolism of furan. Liver contained more furan‐derived radioactivity by far than other tissues after 24 h. Approximately 80% of the radioactivity in liver was not extracted by organic solvents and was associated with protein. There was either no binding to DNA or the furan‐DNA adduct was not stable to the isolation procedure. Repeated daily administration of [¹⁴C]furan resulted in a more or less linear increase in covalent binding through four doses; at this point the amount of nonextractable radioactivity plateaus. Urine contained at least 10 metabolites, again indicating extensive metabolism of the furan ring. From the data obtained in this study it is clear that furan is metabolized to reactive species, apparently primarily in liver, and these intermediates react with protein. The hepatotoxicity resulting from furan exposure may be due to the reaction of furan metabolites with liver macromolecules; the presence of some of these reactive metabolites following chronic exposure to furan may result in cholangiocarcinomas.