Identification of urinary metabolites of isoprene in rats and comparison with mouse urinary metabolites

Isoprene, a major commodity chemical used in production of polyisoprene ela stomers, has been shown to be carcinogenic in rodents. Similar to findings for the structurally related compound butadiene, mice are more susceptible than rats to isoprene-induced toxicity and carcinogenicity. Although differ ences in uptake, and disposition of isoprene in rats and mice have been des cribed, its in vivo biotransformation products have not been characterized in either species. The purpose of these studies was to identify the urinary metabolites of isoprene in Fischer 344 rats and compare these metabolites with those formed in male B6C3F(1) mice. After i.p. administration of 64 mg [C-14]isoprene/kg to rats and mice, isoprene was excreted unchanged in bre ath (similar to 50%) or as urinary metabolites (similar to 32%). In rats is oprene was primarily excreted in urine as 2-hydroxy-2-methyl-3-butenoic aci d (53%), 2-methyl-3-buten-1,2-diol (23%), and the C-1 glucuronide conjugate or 2-methyl-3-buten-1, 2-diol (13%). These metabolites are consistent with preferential oxidation of isoprene's methyl-substituted vinyl group. No ox idation of the unsubstituted vinyl group was observed. In addition to the i soprene metabolites found in rat urine, mouse urine contained numerous othe r isoprene metabolites with a larger percentage (25%) of total urinary radi oactivity associated with an unidentified, polar fraction than in the rat ( 7%). Unlike butadiene, there was no evidence that glutathione conjugation p layed a significant role in the metabolism of isoprene in rats. Because of the unidentified metabolites in mouse urine, involvement of glutathione in the metabolism of isoprene in mice cannot be delineated.