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

人体叶酸生物转化的起始位点在哪里？

• 批准号: BB/F012594/1
• 负责人: David Barrett
• 金额: $ 21.65万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF012594%2F1
• 关键词: Where; initial; site; folic; acid

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.

有证据表明，在受孕前补充叶酸可以预防神经管缺陷，并且流行病学证据表明其他主要疾病的流行与叶酸摄入量和状况不佳有关，这都强调了充足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面粉中强制添加叶酸，以帮助降低未出生婴儿患神经管缺陷（例如脊柱裂）的风险。建议的强化水平为 300 微克/100 克，比美国使用的水平高出两倍，据报道，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，不仅因为可能掩盖老年人维生素 B12 缺乏症，还因为对叶酸基因表达的有害影响，例如叶酸酶可能上调，而叶酸酶是当前抗叶酸化疗的目标（例如二氢叶酸还原酶，DHFR） 。此外，目前存在的疑问是，它可能会加速缺乏 B12 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、增加风险多发性结直肠腺瘤，并增加绝经后妇女乳腺癌的发病率。在当前提案中，IFR 与纽卡斯尔大学和诺丁汉大学之间拟议的合作将提供一个创新和及时的机会，利用来自纽卡斯尔（英国独一无二）对患者进行肝门静脉（HPV）插管，作为“正常”人类肠道和肝脏功能的潜在模型。这个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采用 TIPSS 多普勒监测而不是导管插入术，使得此类研究极难在伦理上证明其合理性。该项目总体上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，而且可以增强我们对人体体内叶酸动力学的理解。这些发现将使人们能够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可能导致血液中这种合成化合物的水平达到不良水平。这些发现将立即用于有关面粉中叶酸强化的持续争论，也可用于食品工业开发替代叶酸丰富食品。

项目成果

Folic acid handling by the human gut: implications for food fortification and supplementation

人体肠道处理叶酸：对食品强化和补充的影响

• DOI: http://dx.10.3945/ajcn.113.080507
• 发表时间: 2014
• 期刊: The American Journal of Clinical Nutrition
• 作者: Patanwala I

Estimation of the 5-methyltetrahydrofolate apparent volume of distribution in humans.

人体中 5-甲基四氢叶酸表观分布容积的估计。

• DOI: http://dx.10.3945/jn.111.143685
• 发表时间: 2012
• 期刊: The Journal of nutrition
• 作者: King MJ