Examination of the differential hepatotoxicity of diallyl phthalate in rats and mice

In this study we confirmed that diallyl phthalate (DAP) is more hepatotoxic to rats than to mice, and we demonstrated the same species difference in toxicity for allyl alcohol (AA). The data suggest that the toxicity of DAP probably results from AA cleaved from DAP. To determine if the species difference in susceptibility to hepatotoxicity resulted from differences in the disposition and metabolism of DAP, Fischer-344 rats and B6C3F1 mice were given [14C]DAP, 1, 10, or 100 mg/kg po or 10 mg/kg iv, and placed in metabolism cages for 24 hr. In rats, 25-30% of the DAP was excreted as CO2, and 50-70% appeared in the urine within 24 hr. In mice, 6-12% of the DAP was excreted as CO2, and 80-90% was excreted in the urine within 24 hr. Monoallyl phthalate (MAP), allyl alcohol, 3-hydroxypropylmercapturic acid (HPMA), and an unidentified polar metabolite (PM) were found in the urine of rats and mice dosed with DAP. The polar metabolite was present in the urine of rats dosed with DAP or AA, indicating that the compound is a metabolite of AA. There was no difference between the species in the quantity of AA excreted, but mice excreted more MAP (39 vs 33%), HPMA (28 vs 17%), and PM (20 vs 8%) than rats. Because DAP is metabolized to AA, a potent periportal hepatotoxicant, and because the mouse produced more HPMA than rats, we postulate that the differential hepatotoxicity of DAP is related to the extent of glutathione conjugation with allyl alcohol or acrolein (the active metabolite of AA).