Characterization of urinary metabolites produced following administration of [1,2,methoxy- super(13)C]-2-methoxyethanol to male F-344 rats and pregnant CD-1 mice

Abstract

The administration of 2-methoxyethanol (2-ME) to pregnant rats, mice, or primates results in developmental and reproductive toxicity. To assess the role of metabolism in the adverse response of 2-ME, super(13)C-NMR spectroscopy was used to detect urinary metabolites produced after administering developmentally toxic (250 mg/kg) and non-toxic (25 mg/kg) doses of [1,2,methoxy- super(13)C] 2-ME to pregnant CD-1 mice and male F-344 rats. The urinary disposition was also examined after dosing pregnant CD-1 mice with 2-ME together with L-serine, D-serine, or acetate (known attenuators of 2-ME embryotoxicity). 2D-NMR methods enabled the assignment of twelve metabolites derived from 2-ME. Pathways involved in forming metabolites include transformation of 2-ME via ethylene glycol, conjugation with glucuronide or sulfate, and oxidation to 2-MAA. Metabolites were also assigned that result from further conversion of 2-MAA to glycine and glucuronide conjugates, as well as metabolites that may be derived following incorporation of 2-methoxyacetyl-CoA into the Krebs cycle or the synthesis of fatty acids. Variations in the percentage of specific urinary metabolites were observed between high and low dose, and between 2-ME alone and 2-ME plus concurrent attenuators. Acetate together with 2-ME reduced the percentage of metabolites incorporated into intermediary metabolism. These data indicate that attenuation of 2-ME teratogenic effects may occur in part by altering the conversion of 2-ME to 2-MAA and by interfering with the conversion of 2-MAA to a coenzyme A thioester (2-methoxyacetyl-CoA).