Cleavage Products of Dietary Carotenoids: Occurrence & Nutritional Function

膳食类胡萝卜素的裂解产物：发生情况

基本信息

批准号：
8018594
负责人：
EARL Howard HARRISON
金额：
$ 47.27万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018594
关键词：
Acids Address Aldehydes All-Trans-Retinol Analytical Chemistry Animals Aryl Hydrocarbon Receptor Beta Carotene Biological Biological Process Carbon Cardiovascular Diseases Carotene Carotenoids Cell Line Cells Cellular Retinol Binding Protein Characteristics Chemicals Color Consumption Cultured Cells Development Diet Dietary Carotenoid Enzymatic Biochemistry Enzyme Kinetics Enzymes Fatty Liver Food Gene Expression Genes Growth Health Hepatic Hepatocyte Human In Vitro Juice Knock-out Knockout Mice Knowledge LNCaP Lead Ligands Liver Lutein Malignant Neoplasms Malignant neoplasm of prostate Metabolic Metabolism Micronutrients Molecular Mus Nuclear Nutritional Oxygenases Parents Pathway interactions Peroxisome Proliferator-Activated Receptors Phenotype Pigments Plasma Play RXR Recombinants Research Retinoic Acid Receptor Risk Role SXR receptor Substrate Specificity Testing Tissues Tomatoes Triglyceride Metabolism U937 Cells Urine Vitamin A Wild Type Mouse base cancer cell cardiovascular disorder risk carotenoic acid cryptoxanthin feeding fruits and vegetables in vivo inhibitor/antagonist interest lipid metabolism lycopene macrophage monocyte mouse model oxidation pi bond public health relevance receptor research study response tool transcription factor zeaxanthin

项目摘要

DESCRIPTION (provided by applicant): Consumption of dietary carotenoids is associated with a decreased risk of cardiovascular disease and cancer. Humans obtain carotenoids in the diet by ingesting fruits and vegetables. Historically, it was thought that the most important role of some carotenoids was their metabolic conversion via cleavage at the central double bond to the essential micronutrient, vitamin A (retinol). There is intense recent interest in the "eccentric cleavage" of dietary carotenoids to apocarotenals and their possible oxidation to apocarotenoic acids. These metabolites of carotenoids may play important roles in the non-vitamin A activities of carotenoids. There are no quantitative analyses of the levels of these compounds in human foods and tissues. Demonstrations of the extent of metabolism of intact carotenoids to these compounds and studies of their mechanisms of action are lacking. We will address these gaps in knowledge. (1) We determine the substrate specificity and characterize the products of the two known human carotenoid-metabolizing enzymes (BCO1 & BCO2). These studies will also establish the relationship of cellular retinol-binding proteins and carotenoid cleavage enzymes in the metabolic function of these enzymes. (2) We will demonstrate the relevance of apocarotenoids in humans using analytical chemistry to characterize the presence and quantify the amounts of apo-carotenals and apocarotenoic acids in human plasma and tissues and in foods. This will be accomplished by quantitation of the immediate post- prandial plasma concentrations of parent carotenoids and metabolites after subjects consume a single serving of tomato juice containing nutritionally relevant amounts of beta-carotene or lycopene as well as by quantitation of steady state concentrations in plasma after 4 weeks of daily consumption. (3) We will use the LNCaP cell, a human prostate cancer cell that demonstrates lycopene-dependent growth inhibition and expresses BCO2 to look for apolycopenals and apolycopenoic acids in lycopene-treated cells to address whether and to what extent lycopene is metabolized in these cells. We will use the human monocyte/macrophage cell, U937, which is growth inhibited and induced to differentiate with carotenoid treatment, to look for metabolism of the parent carotenoids. (4) We will probe the biological (nutritional) function of carotenoid metabolites in multiple ways: (a) we will use cell lines that we have shown have characteristic functional responses to treatment with dietary carotenoids and ask whether these responses are obtained by direct treatment with the cleavage products and (b) we will ask whether these cleavage products and metabolites directly activate or antagonize ligand-dependent transcription factors. (c) We will feed the BCO1 knockout mouse both beta-carotene and lycopene to assess the extent of the metabolism of these carotenoids by BCO2 and the metabolic effects of carotenoid metabolites in the whole animal. The results will enhance our understanding of the molecular basis for the health-promoting effects of diets rich in fruits and vegetables. PUBLIC HEALTH RELEVANCE: Increased consumption of dietary carotenoids is associated with decreased risk of both cardiovascular disease and certain cancers. The proposed research will document the occurrence of new pathways of metabolism of dietary carotenoids (the health-promoting, colored pigments in fruits and vegetables) in humans. The research will also explore possible mechanisms that may explain the basis of the health-promoting effects of these components of the diet.

描述（由申请人提供）：食用饮食类胡萝卜素与心血管疾病和癌症的风险降低有关。人类通过摄入水果和蔬菜而在饮食中获得类胡萝卜素。从历史上看，人们认为某些类胡萝卜素的最重要作用是通过在中央双键上裂解到基本微量营养素的维生素A（视黄醇）的代谢转化。最近，最近对脱型类胡萝卜素的“偏心裂解”及其可能氧化对阿替苯甲酸的兴趣引起了人们的兴趣。这些类胡萝卜素的代谢产物可能在类胡萝卜素的非维生素A活性中起重要作用。对于人类食品和组织中这些化合物的水平没有定量分析。缺乏对这些化合物的完整类胡萝卜素的代谢程度及其作用机理的研究的证明。我们将在知识中解决这些差距。（1）我们确定底物特异性并表征两个已知的人类类胡萝卜素代谢酶的产物（BCO1和BCO2）。这些研究还将在这些酶的代谢功能中建立细胞视黄醇结合蛋白和类胡萝卜素裂解酶的关系。（2）我们将使用分析化学表征人类中的占地苯酚的相关性，以表征并量化人血浆和组织以及食物中的Apo-折线烯和阿替苯甲酸的量。这将通过定量母体胡萝卜素和代谢产物的立即定量后血浆浓度来实现，这些受试者在每天消耗4周后，食用了一份含有营养量的β-胡萝卜素或番茄红素的番茄果汁，这些番茄汁含有营养量的β-胡萝卜素或番茄红素以及血浆后的稳态浓度。（3）我们将使用LNCAP细胞，一种人类前列腺癌细胞，该细胞证明了由番茄红素依赖性生长抑制，并表达BCO2来寻找番茄红素处理的细胞中的叠酰氨基苯甲酸和聚纤维烯酸，以解决这些细胞中是否并在这些细胞中代谢番茄红素。我们将使用人类的单核细胞/巨噬细胞U937，该细胞受到生长的抑制并诱导与类胡萝卜素治疗区分开来，以寻找父型类胡萝卜素的代谢。（4）我们将以多种方式探测类胡萝卜素代谢产物的生物（营养）功能：（a）我们将使用我们所显示的细胞系具有对用饮食类胡萝卜素治疗的特征功能响应，并询问这些反应是通过裂解产物直接治疗而获得的，并且（b）我们将询问这些裂解产物和依赖于这些杂化产物和静止的因素和代替依赖性或代替因素。（c）我们将喂养BCO1敲除小鼠β-胡萝卜素和番茄红素，以评估BCO2的代谢程度以及整个动物中类胡萝卜素代谢物的代谢作用。结果将增强我们对富含水果和蔬菜的饮食促进健康作用的分子基础的理解。公共卫生相关性：饮食类胡萝卜素的消费量增加与心血管疾病和某些癌症的风险降低有关。拟议的研究将记录人类饮食类胡萝卜素代谢的新途径（水果和蔬菜中的健康色素）的新途径。该研究还将探索可能解释饮食这些成分健康促进作用的基础的可能机制。