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

有证据表明，在怀孕前摄入补充叶酸可以预防神经管缺陷，并有流行病学证据表明，其他主要疾病的流行与叶酸摄入量和叶酸摄入不足有关，这些证据都强调了充足的叶酸摄入对公众健康的重要性。英国政府目前正在考虑在英国强制强化面粉中的叶酸，以帮助减少未出生婴儿神经管缺陷（如脊柱裂）的风险。建议的强化水平为300mcg/100g，比美国使用的水平高出两倍，在美国已经有报道称，美国公民在全身血浆循环中存在高浓度未代谢的叶酸。这引起了一些关注，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，如叶酸酶的潜在上调，而叶酸酶是目前抗叶酸化疗的目标（如二氢叶酸还原酶，DHFR）。此外，目前存在的问题是，它是否可能加速b12缺乏老年人的认知能力下降，加速冠状动脉支架内再狭窄的发生率和程度，增加体外受精治疗后的多胎，影响免疫功能，增加多发性结直肠腺瘤的风险，增加绝经后妇女乳腺癌的发病率。IFR与纽卡斯尔大学和诺丁汉大学在当前提案中的拟议合作将提供一个创新和及时的机会，利用纽卡斯尔（英国唯一）肝门静脉（HPV）插管患者的新数据，更好地了解叶酸生理剂量的吸收过程和初始生物转化部位，作为“正常”人类肠道和肝脏功能的潜在模型。这种特殊的机会很可能是短暂的，因为在这些患者中越来越多地引入TIPSS多普勒监测而不是导管置入，使得这种类型的研究极难在伦理上证明。该项目总体上提供了一个独特的机会，不仅验证叶酸是否在未代谢状态下运输到肝脏，而且增强了我们对人体体内叶酸动力学的理解。这些发现将有助于在人群水平上进行更明智的风险评估，以确定叶酸食品强化是否会导致血液中这种合成化合物的不良水平。这一发现将对正在进行的关于面粉中叶酸强化的争论有直接的帮助，也对食品工业开发替代叶酸强化食品有直接的帮助。

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.