A possible mechanism for the formation of 14CO2 via 2-methoxyacetic acid in mice exposed to 14C-labeled 2-methoxyethanol

Small amounts (6-12%) of radioactivity administered by gavage as 14C-labeled 2-methoxyethanol (2-ME) or 2-methoxyacetic acid (2-MAA) to pregnant mice are exhaled as 14CO2 as well as accumulated in tissues that are highly active in the synthesis of macromolecules (Sleet et al., Toxicol. Appl. Pharmacol. 84, 25-35, 1986; Mebus et al., Toxicol. Appl. Pharmacol. 112, 87-94, 1992). In addition, pregnant CD-1 mice similarly administered 13C-labeled 2-ME excrete urinary metabolites that may arise from incorporation of a coenzyme A thioester of 2-MAA into the Krebs cycle, forming methoxycitrate (Sumner et al., Chem. Res. Toxicol. 5, 553-560, 1992). Based on these previously published observations, we propose a mechanism for the further metabolism of methoxycitrate that is consistent with the detection of 14CO2 after administering either [1-14C]2-MAA, [2-14C]2-ME, or [methoxy-14C]2-ME to mice. This postulated pathway may also explain the tissue-specific accumulation of radioactivity arising from [14C]2-ME