PROTECTION AGAINST 2-METHOXYETHANOL-INDUCED TERATOGENESIS BY SERINE ENANTIOMERS - STUDIES OF POTENTIAL ALTERATION OF 2-METHOXYETHANOL PHARMACOKINETICS

Several simple physiological compounds attenuate the teratogenic effects of 2-methoxyethanol (2-ME) when coadministered with 2-ME to mice. The mechanism of this protective action, however, has not been elucidated. Alteration of the kinetics of 2-ME and its oxidation product 2-methoxyacetic acid (2-MAA), the putative ultimate toxicant, was considered. d-Serine, the most efficacious attenuator, and l-serine (both 16.5 mmol/kg po) were examined for their abilities to mitigate 2-ME teratogenicity and to alter the disposition of an oral or sc bolus dose of 2-ME (3.3 mmol/kg containing 6 μCi 2-[methoxy-14C]ethanol) given to CD-1 mice on Gestation Day 11. l-Serine reduced the incidence of malformed fetuses from ≥72% to 26-28%, while only 18 and 9% of fetuses were affected after coadministration of d-serine with sc and po 2-ME, respectively. Changes in the metabolism of orally administered 2-[14C]ME were specific to each enantiomer. d-Serine reduced the amount of 2-methoxy-N-acetylglycine eliminated in the urine to 70-75% of values observed with 2-ME alone, and concurrently increased the amount of urinary 2-MAA. l-Serine induced an initially higher rate of 14CO2 exhalation. Both enantiomers delayed gastrointestinal absorption of 2-ME, and significantly reduced 2-MAA levels in maternal plasma during the first hour after dosing. This resulted in a nonsignificant decrease (10-17%) in total embryonic exposure to 2-MAA. However, when 2-ME was injected sc, maternal plasma 2-ME 2-MAA pharmacokinetics were not affected by serine. In addition, dosing with 2.3 and 1.3 mmol 2-ME/kg sc alone showed that the embryo 2-MAA exposure levels which cause malformations in ≤35% fetuses were considerably lower than those measured following serine plus 3.3 mmol 2-ME/kg (po or sc). These data infer that serine does not protect against 2-ME-induced teratogenicity by altering 2-ME pharmacokinetics and reducing 2-MAA levels in the embryo. © 1991.