Adv Nutr. 2022 Feb 1;13(1):16-33. doi: 10.1093/advances/nmab106.
Vitamin B-12 is a water-soluble vitamin that plays important roles in intermediary metabolism. Vitamin B-12 deficiency has many identifiable causes, including autoimmune and other gastrointestinal malabsorption disorders, dietary deficiency, and congenital defects in genes that are involved in vitamin B-12 trafficking and functions. Another putative cause of vitamin B-12 deficiency is the high-folate-low vitamin B-12 interaction, first suspected as the cause for observed relapse and exacerbation of the neurological symptoms in patients with pernicious anemia who were prescribed high oral doses of folic acid. We propose that this interaction is real and represents a novel cause of vitamin B-12 depletion with specific etiology. We hypothesize that excessive intake of folic acid depletes serum holotranscobalamin (holoTC), thereby decreasing active vitamin B-12 in the circulation and limiting its availability for tissues. This effect is specific for holoTC and does not affect holohaptocorrin, the inert form of serum vitamin B-12. Depletion of holoTC by folic acid in individuals with already low vitamin B-12 status further compromises the availability of vitamin B-12 coenzymes to their respective enzymes, and consequently a more pronounced state of biochemical deficiency. This hypothesis is drawn from evidence of observational and intervention studies of vitamin B-12-deficient patients and epidemiological cohorts. The evidence also suggests that, in a depleted state, vitamin B-12 is diverted to the hematopoietic system or the kidney. This most likely reflects a selective response of tissues expressing folate receptors with high affinity for unmetabolized folic acid (UMFA; e.g., hematopoietic progenitors and renal tubules) compared with those tissues (e.g., liver) that only express the reduced folate carrier, which is universally expressed but has poor affinity for UMFA. The biochemical and physiological mechanisms underlying this interaction require elucidation to clarify its potential public health significance.
维生素 B-12 是一种水溶性维生素，在中间代谢中发挥重要作用。维生素 B-12 缺乏有许多可识别的原因，包括自身免疫和其他胃肠道吸收不良疾病、饮食缺乏以及参与维生素 B-12 转运和功能的基因先天缺陷。维生素 B-12 缺乏的另一个潜在原因是高叶酸低维生素 B-12 相互作用，最初怀疑是导致服用高剂量叶酸的恶性贫血患者的神经症状复发和恶化的原因。我们提出这种相互作用是真实存在的，并代表了一种新的、具有特定病因的维生素 B-12 耗竭的原因。我们假设，这种相互作用是真实存在的，代表了一种新的、具有特定病因的维生素 B-12 耗竭的原因。我们假设，过量摄入叶酸会耗尽血清全钴胺素（holoTC），从而减少循环中的活性维生素 B-12，限制其组织可用性。这种效应是针对 holoTC 的，不会影响血清维生素 B-12 的惰性形式 holohaptocorrin。在已经处于低维生素 B-12 状态的个体中，叶酸耗尽 holoTC 会进一步损害维生素 B-12 辅酶与其各自酶的可用性，从而导致更明显的生化缺乏状态。这一假设是基于对维生素 B-12 缺乏患者的观察性和干预性研究以及流行病学队列的证据得出的。这些证据还表明，在耗竭状态下，维生素 B-12 被转移到造血系统或肾脏。这很可能反映了对未代谢叶酸（UMFA；例如，造血祖细胞和肾小管）具有高亲和力的叶酸受体表达组织的选择性反应，而不是仅表达还原叶酸载体的组织（例如，肝脏），还原叶酸载体普遍表达，但对 UMFA 的亲和力较差。这种相互作用的生化和生理机制需要阐明，以澄清其潜在的公共卫生意义。
