Where is the initial site of folic acid biotransformation in humans?

足够的叶酸摄入量对公共健康的重要性是强调的证据表明，神经管缺陷可以通过在怀孕前摄入补充叶酸来预防，以及流行病学证据将其他主要疾病的患病率与叶酸摄入量不足和状态联系起来。英国政府目前正在考虑在英国强制性强化面粉中的叶酸，以帮助降低未出生婴儿患神经管缺陷（如脊柱裂）的风险。建议的强化水平为300 mcg/100 g，是美国使用水平的两倍，美国已经有报告称，美国公民的全身血浆循环中存在高浓度的未代谢叶酸。这引起了一些担忧，不仅是因为老年人维生素B12缺乏的潜在掩盖，而且对叶酸基因表达的有害影响，例如叶酸酶的潜在上调，叶酸酶是目前抗叶酸化疗的靶点（例如二氢叶酸还原酶，DHFR）。此外，目前存在的问题是，它可能加速B12缺乏的老年人的认知能力下降，加速冠状动脉支架内再狭窄的速度和程度，增加体外受精治疗后的多胞胎，影响免疫功能，增加多发性结直肠腺瘤的风险，并增加绝经后妇女乳腺癌的发病率。IFR、以及纽卡斯尔和诺丁汉大学在当前提案中将提供一个创新和及时的机会，利用纽卡斯尔肝门静脉（HPV）插管患者的新数据，更好地了解生理剂量叶酸的吸收过程和初始生物转化部位（在英国是独一无二的）作为“正常”人类肠道和肝脏功能的潜在模型。这种特殊的机会可能是短暂的，因为越来越多的TIPSS多普勒监测这些患者，而不是导管插入，使这种类型的研究非常难以证明伦理。总的来说，该项目提供了一个独特的机会，不仅可以验证叶酸是否以未代谢状态转运到肝脏，还可以增强我们对人体体内叶酸动力学的理解。这些发现将使在人群水平上进行更知情的风险评估，以决定食品中添加叶酸是否可能导致血液中这种合成化合物的不良水平。这些发现将立即用于正在进行的关于面粉叶酸强化的辩论，以及食品工业开发替代叶酸强化食品。

The importance of adequate folate intake to public health is underlined by evidence that neural tube defects can be prevented by intake of supplemental folic acid before conception, as well as epidemiological evidence linking the prevalence of other major diseases to poor folate intake and status. The UK Government is currently considering the mandatory folic acid fortification of flour in the UK in order to help reduce the risk of neural tube defects (such as spina bifida) in unborn babies. The suggested fortification level of 300mcg/100g is two-fold higher than being used in the USA, where there has already been reports of high concentrations of unmetabolised folic acid in the systemic plasma circulation in US citizens. This has raised some concerns, not merely from the potential masking of vitamin B12 deficiency in the elderly but deleterious affects on folate gene expression such as a potential upregulation of folate enzymes that are current targets for anti-folate chemotherapy (e.g. dihydrofolate reductase, DHFR). Moreover, there are current question maks regarding its potential to accelerate cognitive decline in B12-deficient elderly, to accelerate the rate and extent of coronary in-stent restenosis, increase multiple births after invitro-fertilisation treatment, to affect immune function, ito ncrease risk of multiple colorectal adenomas, and to increase incidence of breast cancer in post-menopausal women. The proposed collaboration between IFR, and the Universities of Newcastle and Nottingham in the current proposal will provide an innovative and timely opportunity to develop a better fundemental understanding of the process of absorption and site of initial biotransformation of physiological doses of folic acid using new data from hepatic portal vein (HPV) cannulated patients in Newcastle (uniquely in the UK) as a potential model of 'normal' human intestinal and liver function. This exceptional opportunity is likely to be short-lived because of the increasing introduction of TIPSS Doppler monitoring in these patients rather than catheterisation, making this type of study extremely difficult to justify ethically. The project overall provides a unique opportunity not only to verify whether folic acid is transported to the liver in an unmetabolised state but also enhancing our understanding of in vivo folate kinetics in humans. These findings would enable a more informed risk assessment to be conducted at a population level to decide whether food fortification with folic acid might lead to undesirable levels of this synthetic compound in the blood. The findings will be of immediate use to the ongoing debate regarding folic acid fortification of flour, and also to the food industry in developing alternate folate enriched foods.