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Vitamin C (ascorbic acid) Biochemistry and Molecular Biology

维生素 C（抗坏血酸）生物化学和分子生物学

基本信息

批准号：
7734195
负责人：
MARK A LEVINE
金额：
$ 40.22万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Summary Based on extensive pharmacokinetics data from this laboratory, we have learned that Vitamin C concentrations are tightly controlled in healthy humans as a function of vitamin C dose. Three physiologic processes appear to be responsible: intestinal absorption, tissue transport, and renal filtration/reabsorption. In particular, our pharmacokinetics data indicate that the renal threshold of excretion plays a key role in the observed tight control of vitamin C concentrations in plasma and tissues. We hypothesized that Slc23a1, the vitamin C epithelial transporter expressed in kidney, is responsible for tight control. To test this we created a mouse null for the Slc23a1 gene. Inbred C57bL/6J wild type, Slc23a1+/- and Slc23a1-/- mice were generated on a Balb/c background. After weaning, growth rates of wild type, Slc23a1+/- and Slc23a1-/- mice were indistinguishable. Urine vitamin C fractional excretion was 7-10 fold higher in Slc23a1-/- mice compared to wildtype littermates. Corresponding plasma ascorbic acid concentrations in slc23a1-/- mice were 50-70% lower than in wild type littermates. In slc23a1-/- mice, neuronal tissue ascorbate concentrations levels were unaffected by the depressed plasma ascorbate levels, whereas all other tissues trended downwards. These data show that Slc23a1 is responsible for tight control of vitamin C, via regulation of renal threshold of excretion. The asymmetric response of tissues to decreased plasma vitamin C may represent redistribution of vitamin C to protect brain function. Active investigation is underway to describe the consequences of the vitamin C renal leak in these animals. Humans with Slc23a1 single nucleotide polymorphisms that decrease activity of the renal vitamin C transporter might also have altered vitamin C pharmacokinetics due to a renal leak, and therefore require additional vitamin C intake. These findings have unique implications for recommended dietary allowances, because they may need to account for individual genetic differences. Vitamin C is accumulated in human lymphocytes and monocytes, but its function is unknown. We hypothesized that vitamin C might regulate gene transcription in these cells. To investigate, we studied lymphocyte-enriched and monocyte-enriched cell populations isolated from whole blood by in vivo apheresis from 11 healthy women who were 19-27 years old. Cells were isolated from the same women at steady state at each of the following daily vitamin C doses: 30mg; 60 mg; 100 mg; and 1000 or 2500 mg. Comparisons to determine significant changes in gene expression were performed using mRNA from the same subjects at different doses, with RNA obtained at 30 mg as baseline. Gene expression was analyzed using Affymatrix arrays, statistical and pathway software (GeneSpring, Partek, GeneGo), and confirmed by quantitative real time PCR. The data showed that in monocyte enriched populations, higher Vitamin C doses significantly increased expression of multiple components of three similar pathways: CD28 signaling; ICOS-ICOSL signaling; and T cell receptor signaling. Also, in monocyte enriched populations, the EGF signaling pathway was significantly increased with increasing vitamin C doses. In lymphocytes, fewer pathways were affected compared to monocytes. These analyses reveal novel functions of vitamin C on gene transcription in circulating cells in human plasma. These are the first data describing changes in gene expression as a function of varying nutrient concentrations in the same human subjects, for any nutrient.

摘要基于本实验室广泛的药代动力学数据，我们了解到，在健康人体内，维生素C浓度作为维生素C剂量的函数受到严格控制。似乎有三个生理过程起作用：肠道吸收、组织转运和肾滤过/重吸收。特别是，我们的药代动力学数据表明，肾脏排泄阈值在观察到的血浆和组织中维生素C浓度的严格控制中起着关键作用。我们推测，肾脏中表达的维生素C上皮转运蛋白SLc23a1负责严格控制。为了测试这一点，我们为Slc23a1基因创造了一个小鼠零。近交系C57BL/6J野生型、Slc23a1+/-和Slc23a1-/-小鼠是在Balb/c背景下产生的。断奶后，野生型、Slc23a1+/-和Slc23a1-/-小鼠的生长速度没有明显差别。SLc23a1/-小鼠的尿中维生素C排泄量是野生型小鼠的7-10倍。Slc23a1-/-小鼠相应的血浆抗坏血酸浓度比野生型仔鼠低50-70%。在slc23a1-/-小鼠中，神经元组织抗坏血酸水平不受压低的血浆抗坏血酸水平的影响，而所有其他组织呈下降趋势。这些数据表明，SLc23a1通过调节肾脏排泄阈值，负责严格控制维生素C。组织对血浆维生素C降低的不对称反应可能代表了维生素C的重新分配，以保护大脑功能。目前正在进行积极的调查，以描述这些动物体内维生素C肾泄漏的后果。SLc23a1单核苷酸多态降低肾脏维生素C转运体活性的人也可能由于肾脏渗漏而改变维生素C的药代动力学，因此需要额外的维生素C摄入量。这些发现对推荐的饮食摄入量具有独特的影响，因为它们可能需要考虑个体遗传差异。维生素C在人的淋巴细胞和单核细胞中积累，但其功能尚不清楚。我们假设维生素C可能调节这些细胞中的基因转录。为了进行研究，我们研究了11名19-27岁的健康女性通过体内分离从全血中分离出的淋巴细胞和单核细胞富集群。以下列每日维生素C剂量：30毫克、60毫克、100毫克、1000毫克或2500毫克，在稳定状态下从同一妇女身上分离细胞。使用来自相同受试者的不同剂量的RNA进行比较，以30 mg的RNA为基线，确定基因表达的显著变化。用AffyMatrix阵列、统计和路径分析软件(GeneSpring、Partek、GeneGo)分析基因表达，并用实时定量聚合酶链式反应进行确认。数据显示，在单核细胞丰富的人群中，较高的维生素C剂量显著增加了三个类似途径的多个组成部分的表达：CD28信号；ICOS-ICOSL信号；和T细胞受体信号。此外，在单核细胞丰富的人群中，EGF信号通路随着维生素C剂量的增加而显著增加。在淋巴细胞中，与单核细胞相比，受影响的途径较少。这些分析揭示了维生素C对人体血浆循环细胞中基因转录的新功能。这是第一批描述基因表达变化的数据，这些变化是同一受试者中任何营养物质的不同营养浓度的函数。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dehydroascorbate and glucose are taken up into Arabidopsis thaliana cell cultures by two distinct mechanisms.

DOI：
10.1016/j.febslet.2008.07.001
发表时间：
2008-08-06
期刊：
FEBS LETTERS
影响因子：
3.5
作者：
Horemans, N.;Szarka, A.;De Bock, M.;Raeymaekers, T.;Potters, G.;Levine, M.;Banhegyi, G.;Guisez, Y.
通讯作者：
Guisez, Y.

Vitamin C and myocardial infarction: the heart of the matter.