FIGURE 11.

Hypothesized effects of excess folic acid on serum holoTC and metabolic and physiological functions in vitamin B-12 insufficiency/deficiency. (A) HoloTC (TC-B12) delivers vitamin B-12 to all tissues of the body, primarily by receptor-mediated endocytosis via the TC-B12 receptor, CD320 (green squares). In addition, in the kidney, TC-B12 is filtered through the renal glomeruli and then taken up by renal proximal tubule cells via the megalin/cubilin/amnionless receptor complex (blue square), thus retaining vitamin B-12 by limiting its excretion in the urine. Within cells, the TC-B12 complex enters lysosomes in which the vitamin B-12 is released from TC and then processed to serve as a cofactor in either of 2 metabolic reactions: 1) as methyl-B12 in the cytosolic remethylation of homocysteine to methionine, and 2) as deoxyadenosyl-B12 (ado-B12) in the mitochondrial conversion of methylmalonyl CoA (MMCoA) to succinyl CoA. In vitamin B-12 insufficiency, serum TC-B12 concentrations are low, thus leading to low cellular vitamin B-12 uptake, impairment of the 2 vitamin B-12–dependent metabolic reactions, and increases in serum Hcy and MMA. As insufficiency progresses to deficiency, the classical pathophysiological consequences include impaired hematopoiesis leading to reduced reticulocyte synthesis and neurodegeneration in the central and peripheral nervous systems. (B) It is hypothesized that exposure to excess folic acid (via supplements and fortified foods) causes exacerbation of vitamin B-12 deficiency by binding to folic acid receptors (FR; red triangles) in the bone marrow and the renal proximal tubule cells. This leads to diversion of the limited supply of serum TC-B12 (depicted by thick black arrows) to the bone marrow to support folic acid–mediated hematopoiesis and reticulocyte formation, or into the urine by possibly interfering with TC-B12 uptake via the megalin/cubilin/amnionless receptor complex in the renal proximal tubule cells or by some other mechanism yet to be elucidated. The TC-B12 is diverted away from other tissues (e.g., liver and brain; depicted by thin dashed arrows). This leads to accentuated elevations in Hcy and MMA concentrations in serum (also depicted by thick black arrows) and exacerbation of neurodegeneration. B12, vitamin B-12; Hcy, homocysteine; holoTC, holotranscobalamin; MMA, methylmalonic acid; THF, tetrahydrofolate..