Role of cytochrome P450 2E1 in the metabolism of acrylamide and acrylonitrile in mice

Acrylonitrile (AN) and acrylamide (AM) are commonly used in the synthesis o f plastics and polymers. In rodents, AM and AN are metabolized to the epoxi des glycidamide and cyano-ethylene oxide, respectively. The aim of this stu dy was to determine the role of cytochrome P450 in the metabolism of AM and AN in vivo. Wild-type (WT) mice, WT mice pretreated with aminobenzotriazol e (ABT, 50 mg/kg ip, 2 h pre-exposure), and mice devoid of cytochrome P450 2E1 (P450 2E1-null) were treated with 50 mg/kg [C-13]AIM po. WT mice and P4 50 2E1-null mice were treated with 2.5 or 10 mg/kg [C-13]AN po. Urine was c ollected for 24 h, and metabolites were characterized using C-13 NMR. WT mi ce excreted metabolites derived from the epoxides and from direct GSH conju gation with AM or AN. Only metabolites derived from direct GSH conjugation with AM or AN were observed in the urine from ABT-pretreated WT mice and P4 50 2E1-null mice. On the basis of evaluation of urinary metabolites at thes e doses, these data suggest that P450 2E1 is possibly the only cytochrome P 450 enzyme involved in the metabolism of AM and AN in mice, that inhibiting total P450 activity does not result in new pathways of non-P450 metabolism of AM, and that mice devoid of P450 2E1 do not excrete metabolites of AM o r AN that would be produced by oxidation by other cytochrome P450s. P450 2E 1-null mice may be an appropriate model for the investigation of the role o f oxidative metabolism in the toxicity or carcinogenicity of these compound s.