The contribution of genetic factors to inter-individual variability in dietary isoflavone absorption and metabolism

在食用高豆制品的人群中，某些疾病，包括癌症和心血管疾病的发病率较低，可能是由于大豆中被称为异黄酮的成分。在动物模型和培养细胞中证明大豆、大豆提取物和分离异黄酮具有生物活性的研究，提供了与表明这种保护作用的基于人群的研究相一致的证据。对个体受试者如何吸收和代谢大豆异黄酮的研究表明，不同个体之间存在相当大的差异，而这种差异可能决定了食用富含大豆的饮食对特定个体的健康益处的程度。因此，为了能够就富含大豆的饮食或服用异黄酮补充剂的潜在有益效果给出明智的建议，有必要了解决定为什么不同个体在处理饮食异黄酮方面存在差异的因素。变异的一个主要来源可能是个体基因组成的差异，这与参与异黄酮在肠道吸收的转运蛋白有关，也与异黄酮一旦被吸收后负责代谢的酶有关。因此，该项目的目的是研究个体之间的特定遗传差异如何影响单次口服异黄酮的吸收效率和代谢。受试者将从300名健康的绝经前高加索女性中选择150名，使用从血液样本中制备的DNA进行筛选，以获得我们希望研究的基因差异的样本组。使用这一受限制的人群将限制异黄酮吸收和代谢的可变性，这些可变性是由非遗传因素或我们将研究的遗传差异引起的。志愿者将在摄入含有大豆浓缩物的胶囊后24小时内收集所有尿液，并在服用补充剂后3小时提供血液样本。将测量这些样品中的异黄酮浓度，以表明吸收和代谢的效率。有证据表明，异黄酮的一些代谢是在口腔中进行的，在预防口腔癌方面可能特别重要。因此，我们也将通过从所有志愿者的口腔上皮表面收集的细胞中提取的提取物，研究与这种形式的代谢活动和标记化合物的代谢率相关的一些基因的变异性之间是否存在任何关系。如果DNA序列中特定位置的个体之间的遗传变异与异黄酮吸收和代谢效率之间的联系得以确立，将增加关于膳食异黄酮摄入对个体间有益影响的累积数据，并将对设计旨在确定遗传变异如何影响膳食异黄酮对疾病风险标记物的影响的未来研究具有重要意义。

Lower incidence of some diseases, including cancer and cardiovascular disease, in populations who consume diets with a high content of soyabean products may be due to components of the soyabean known as isoflavones. Studies demonstrating biological activity of soyabean and soyabean extracts and isolated isoflavones in animal models and cultured cells provide evidence consistent with population-based studies that indicate such protective effects. Studies examining how individual subjects absorb and metabolise soyabean isoflavones reveal considerable variability between different individuals, and this variability is likely to determine the degree to which consumption of a soyabean-rich diet may offer health benefits to particular individuals. To be able to give informed advice on the potential beneficial effects of a soyabean-rich diet, or of taking isoflavone supplements, therefore, it is essential to understand factors that determine why different individials differ in their handling of dietary isoflavones. One major source of variability is likely to be differences in individuals' genetic make up with respect to the transporter proteins involved in the absorption of the isoflavones across the intestine and in enzymes responsible for metabolism of the isoflavones once absorbed. The aim of this project, therefore, is to study how specific genetic differences between individuals may affect the efficiency of absorption and the metabolism of isoflavones taken as a single oral dose. Subjects will be 150 healthy, premenopausal, Caucasian females selected from an initial group of 300 screened using DNA prepared from blood samples to obtain a sample group who vary with respect to differences in the genes we wish to study. The use of this restricted population group will limit variability in isoflavone absorption and metabolism resulting from non-genetic factors or from genetic differences additional to those we will study. Volunteers will collect all urine for 24 hours following the ingestion of capsules containing soyabean concentrate and will also give a blood sample 3 hours after taking the supplement. Isoflavone concentrations will be measured in these samples to indicate the efficiency of absorption and metabolism. There is evidence to indicate that some metabolism of the isoflavones takes place in the mouth and may be particularly important in terms of protection against oral cancer. We will also, therefore, investigate if there is any relationship between variability in some of the genes we will study that are related to this form of metabolic activity and rates of metabolism of a marker compound by extracts prepared from cells collected form the epithelial surface of the mouth by all volunteers. A link between genetic variability between individuals at specific locations in the DNA sequence and efficiency of isoflavone absorption and metabolism, should this be established, will add to a body of accumulating data concerning interindividual beneficial effects of dietary isoflavone intake and will have important implications for the design of future studies aimed at determining how genetic variability affects the influence of dietary isoflavones on markers of disease risk.