Perspective: The High-Folate-Low-Vitamin B-12 Interaction Is a Novel Cause of Vitamin B-12 Depletion with a Specific Etiology-A Hypothesis.
Perspective: The High-Folate-Low-Vitamin B-12 Interaction Is a Novel Cause of Vitamin B-12 Depletion with a Specific Etiology-A Hypothesis.
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DOI：
10.1093/advances/nmab106
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发表时间：
2021-10
影响因子：
9.3
通讯作者：
J. Selhub;Joshua W. Miller;A. Troen;J. Mason;P. Jacques
中科院分区：
文献类型：
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作者：
J. Selhub;Joshua W. Miller;A. Troen;J. Mason;P. Jacques
维生素B-12是一种在中间代谢中起重要作用的水溶性维生素。维生素B-12缺乏有许多可识别的原因，包括自身免疫性和其他胃肠道吸收不良障碍，饮食不足，以及与维生素B-12运输和功能有关的基因先天缺陷。维生素B-12缺乏的另一个假定原因是高叶酸和低维生素B-12的相互作用，最初被怀疑是服用高剂量叶酸的恶性贫血患者观察到的复发和神经症状恶化的原因。我们认为这种相互作用是真实的，并代表了维生素B-12枯竭的一个新原因，具有特定的病因。我们假设，过量摄入叶酸会耗尽血清全反式钴胺(HoloTC)，从而减少循环中的活性维生素B-12，限制其在组织中的可获得性。这种效应是全反式胆固醇所特有的，并不影响全脂结合蛋白，即血清中维生素B-12的惰性形式。在维生素B-12水平已经较低的个体中，叶酸耗尽全脂胆固醇会进一步损害维生素B-12辅酶对各自酶的可用性，从而导致更明显的生化缺陷状态。这一假说来自对维生素B-12缺乏患者和流行病学队列的观察和干预研究的证据。证据还表明，在耗尽的状态下，维生素B-12被转移到造血系统或肾脏。这很可能反映了表达叶酸受体的组织对未代谢的叶酸(UMFA)具有高亲和力的组织，与那些只表达还原叶酸载体的组织(如肝脏)相比，表达叶酸受体的组织对未代谢的叶酸(UMFA；例如造血祖细胞和肾小管)具有选择性反应。这种相互作用背后的生化和生理机制需要澄清，以澄清其潜在的公共卫生意义。
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.