• Journal Article

Dose-dependent urinary excretion of acrylonitrile metabolites by rats and mice

Citation

Kedderis, G. L., Sumner, S., Held, S. D., Batra, R., Turner, M. J., Roberts, A. E., & Fennell, T. (1993). Dose-dependent urinary excretion of acrylonitrile metabolites by rats and mice. Toxicology and Applied Pharmacology, 120(2), 288-297.

Abstract

The dose dependence of the urinary excretion of acrylonitrile (ACN) metabolites was studied after oral administration of [2,3-14C]ACN to male F-344 rats (0.09 to 28.8 mg/kg) and male B6C3F1 mice (0.09 to 10.0 mg/kg). Urine was the major route of excretion of ACN metabolites (77 to 104% of the dose), with less than 8% of the dose excreted in the feces. Reverse-phase HPLC analysis of urine from treated animals indicated five major components (1 through 5 in order of elution) that accounted for 75 to 100% of the total urinary radioactivity. Component 4 was observed in the urine of ACN-treated mice but was only present in trace amounts in the urine of ACN-treated rats. Components 1, 2, and 3 were present in the urine of animals administered [2,3-14C]cyanoethylene oxide (CEO), indicating that these components were derived from the epoxide metabolite of ACN. The ACN urinary metabolites were isolated by HPLC and identified by chromatographic and mass spectral analysis. Component 5 was N-acetyl-S-(2-cyanoethyl)cysteine and component 4 was S-(2-cyanoethyl)thioacetic acid, both derived from the glutathione (GSH) conjugate of ACN. Component 3 contained N-acetyl-S-(2-hydroxyethyl)cysteine, N-acetyl-S-(carboxymethyl)cysteine, and N-acetyl-S-(1-cyano-2-hydroxyethyl)cysteine. Component 2 was thiodiglycolic acid. These urinary metabolites are derived from catabolism of the GSH conjugates of CEO. The polar component 1 was not identified. These results demonstrate that GSH conjugation is the major disposition pathway of ACN. The excretion of metabolites derived from CEO was an approximately linear function of dose in both species, whereas the excretion of N-acetyl-S-(2-cyanoethyl)cysteine increased nonlinearly with dose. This nonlinearity indicates the presence of a saturable pathway competing with glutathione for ACN, most likely the cytochrome P450-dependent oxidation of ACN. Thiodiglycolic acid was formed 10-fold more in mice than in rats, but this species difference in the oxidative processing of GSH conjugates is probably not of toxicological significance. The ratio of ACN epoxidation to GSH conjugation was 0.50 in rats and 0.67 in mice. This species difference in ACN oxidation could have important toxicological implications, since CEO is believed to mediate the carcinogenic effects of ACN