Absorption and Tissue Distribution of Folate Forms in Rats: Indications for Specific Folate Form Supplementation during Pregnancy

Abstract

Food fortification and folic acid supplementation during pregnancy have been implemented as strategies to prevent fetal malformations during pregnancy. However, with the emergence of conditions where folate metabolism and transport are disrupted, such as folate receptor alpha autoantibody (FRαAb)-induced folate deficiency, it is critical to find a folate form that is effective and safe for pharmacologic dosing for prolonged periods. Therefore, in this study, we explored the absorption and tissue distribution of folic acid (PGA), 5-methyl-tetrahydrofolate (MTHF), l-folinic acid (levofolinate), and d,l-folinic acid (Leucovorin) in adult rats. During absorption, all forms are converted to MTHF while some unconverted folate form is transported into the blood, especially PGA. The study confirms the rapid distribution of absorbed folate to the placenta and fetus. FRαAb administered, also accumulates rapidly in the placenta and blocks folate transport to the fetus and high folate concentrations are needed to circumvent or overcome the blocking of FRα. In the presence of FRαAb, both Leucovorin and levofolinate are absorbed and distributed to tissues better than the other forms. However, only 50% of the leucovorin is metabolically active whereas levofolinate is fully active and generates higher tetrahydrofolate (THF). Because levofolinate can readily incorporate into the folate cycle without needing methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) in the first pass and is relatively stable, it should be the folate form of choice during pregnancy, other disorders where large daily doses of folate are needed, and food fortification.

Brain Uptake of Folate Forms in the Presence of Folate Receptor Alpha Antibodies in Young Rats: Folate and Antibody Distribution

“…At this point, a process must exist to increase the local MTHF concentration because MTHF is taken up by hepatocytes primarily via the RFC, which is a low-affinity, high-capacity transporter for MTHF storage in the liver. When a large dose is administered, substantial amounts of unconverted folate form would appear in the blood and potentially both unconverted and the form converted to MTHF would be available for tissue uptake, including the brain [25]. Excess folate is rapidly excreted primarily via the kidneys.…”

“…In a rat model of exposure to rat FRα specific antibodies (FRαAb) during gestation, we have shown antibody accumulation in the placenta and blocking of folate transport to the fetus [25]. Pups born to these mothers have shown learning and behavioral deficits that can be prevented with folinic acid [26].…”

Recent Advances in Folates and Autoantibodies against Folate Receptors in Early Pregnancy and Miscarriage

“…FRAbs target the placenta and embryos, and have been shown to inhibit folate transport from rats to their fetuses, leading to folate deficiency during pregnancy [110,132]. Da Costa et al demonstrated that the intraperitoneal administration of a low dose of antiserum to FRs, on the 8th day of gestation, increased the embryo resorption rate in rats, which could be rescued by folinic acid; however, it was dexamethasone instead of folinic acid that reversed the embryo-lethal effect induced by a larger dose of antiserum [26].…”

Behavioral deficits in rats exposed folate receptor alpha antibodies in utero are transmitted to the next generation

“…Treatment with higher doses of alternative forms of folate such as d,l-folinic acid or methylfolate can mitigate some of these effects and can improve verbal communication in these children 19 . Evidence also suggests that folinic acid is most effective in reaching the CSF and brain when FRαAb is present in children 20 .…”