Hyperglycinemia due to folate deficiency in rats: evidence for the lack of involvement of the hepatic glycine cleavage system

In addition to a well-recognized hyperhomocysteinemic state, folate deficiency also leads to profound hyperglycinemia. To further characterize the latter observation, two trials were conducted using a folate-deficient rat model to (1) determine the sensitivity of plasma glycine to folate repletion and (2) test the hypothesis that hyperglycinemia results from a reduced flux through the folate-dependent glycine cleavage system (GCS). Weanling male Sprague–Dawley rats were used, and they consumed an amino acid-defined diet with either 0 (FD) or 1 (FA) mg/kg of crystalline folic acid. In Trial 1, 30 rats consumed the FD diet for 28 days. Rats then consumed diets containing 0.1, 0.2, 0.3 or 0.4 mg/kg of folic acid for 14 days before termination. In Trial 2, 16 rats were allocated to receive either the FA (n=8) or FD (n=8) diet for 30 days before termination. Liver mitochondria were isolated and flux through the GCS (measured as ¹⁴CO₂ production from 1-¹⁴C-glycine) was determined. Plasma from blood collected at termination was analyzed for folate, homocysteine and glycine. In Trial 1, both homocysteine and glycine responded linearly to increased dietary folic acid (milligrams per kilogram) levels (P<.05). In Trial 2, plasma folate (FA=25.85 vs. FD=0.66; S.E.M.=1.4 μM), homocysteine (FA=11.1 vs. FD=55.3; S.E.M.=1.7 μM) and glycine (FA=564 vs. FD=1983; S.E.M.=114 μM) were significantly affected by folate deficiency (P<.0001). However, glycine flux through hepatic GCS was not affected by folate deficiency (P>.05). These results provide evidence that in a folate-deficient rat model, both homocysteine and glycine are sensitive to dietary folic acid levels; however, the observed hyperglycinemia does not appear to be related to a reduced flux through the hepatic GCS.