Cleavage Products of Dietary Carotenoids: Occurrence & Nutritional Function

膳食类胡萝卜素的裂解产物：发生情况

• 批准号: 8403982
• 负责人: EARL Howard HARRISON
• 金额: $ 35.93万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403982
• 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; 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; 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; prostate cancer cell; public health relevance; receptor; research study; response; tool; transcription factor; zeaxanthin

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.

描述（由申请人提供）：膳食类胡萝卜素的消耗与心血管疾病和癌症风险降低相关。人类通过摄入水果和蔬菜从饮食中获取类胡萝卜素。从历史上看，人们认为某些类胡萝卜素最重要的作用是通过中心双键的裂解进行代谢转化为必需的微量营养素维生素 A（视黄醇）。最近人们对膳食类胡萝卜素“偏心裂解”为脱辅基胡萝卜素及其可能氧化为脱辅基胡萝卜素酸产生了浓厚的兴趣。类胡萝卜素的这些代谢物可能在类胡萝卜素的非维生素A活性中发挥重要作用。目前还没有对人类食物和组织中这些化合物的含量进行定量分析。目前还缺乏完整类胡萝卜素代谢为这些化合物的程度的证明及其作用机制的研究。我们将解决这些知识差距。 (1) 我们确定底物特异性并表征两种已知的人类类胡萝卜素代谢酶（BCO1 和 BCO2）的产物。这些研究还将建立细胞视黄醇结合蛋白和类胡萝卜素裂解酶在这些酶的代谢功能中的关系。 (2) 我们将使用分析化学来表征脱辅基胡萝卜素和脱辅基胡萝卜素在人类血浆、组织和食品中的存在并定量其含量，从而证明类脱辅基胡萝卜素在人类中的相关性。这将通过受试者食用一份含有营养相关量的β-胡萝卜素或番茄红素的番茄汁后立即定量母体类胡萝卜素和代谢物的餐后血浆浓度以及通过定量血浆中的稳态浓度来完成。 4 周每日食用量。 (3) 我们将使用 LNCaP 细胞（一种表现出番茄红素依赖性生长抑制并表达 BCO2 的人类前列腺癌细胞）来寻找经番茄红素处理的细胞中的脱多酚醛和脱多酚酸，以了解番茄红素在这些细胞中是否代谢以及代谢程度。我们将使用人类单核细胞/巨噬细胞 U937 来寻找母体类胡萝卜素的代谢，该细胞生长受到抑制，并通过类胡萝卜素处理诱导分化。 (4) 我们将以多种方式探讨类胡萝卜素代谢物的生物（营养）功能： (a) 我们将使用已证明对膳食类胡萝卜素治疗具有特征性功能反应的细胞系，并询问这些反应是否是通过直接治疗获得的对于裂解产物，（b）我们将询问这些裂解产物和代谢物是否直接激活或拮抗配体依赖性转录因子。 (c) 我们将给 BCO1 敲除小鼠喂食 β-胡萝卜素和番茄红素，以评估 BCO2 代谢这些类胡萝卜素的程度以及类胡萝卜素代谢物在整个动物中的代谢影响。研究结果将加深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。

项目成果

β-Apo-13-carotenone regulates retinoid X receptor transcriptional activity through tetramerization of the receptor.

β-Apo-13-胡萝卜素通过受体的四聚化调节类维生素A X 受体的转录活性。

• DOI: 10.1074/jbc.m114.610501
• 发表时间: 2014
• 期刊: The Journal of biological chemistry
• 作者: Sun,Jian;Narayanasamy,Sureshbabu;CurleyJr,RobertW;Harrison,EarlH
• 通讯作者: Harrison,EarlH

Novel cell culture medium for use in oxidation experiments provides insights into mechanisms of endothelial cell-mediated oxidation of LDL.

用于氧化实验的新型细胞培养基提供了对内皮细胞介导的 LDL 氧化机制的见解。

• DOI: 10.1007/bf02577525
• 发表时间: 2000
• 期刊: In vitro cellular & developmental biology. Animal
• 作者: Dugas,TR;Morel,DW;Harrison,EH
• 通讯作者: Harrison,EH

Distributions of carotenoids and alpha-tocopherol among lipoproteins do not change when human plasma is incubated in vitro.

当人血浆在体外培养时，类胡萝卜素和α-生育酚在脂蛋白中的分布不会改变。

• DOI: 10.1093/jn/125.10.2610
• 发表时间: 1995
• 期刊: The Journal of nutrition
• 作者: Romanchik,JE;Morel,DW;Harrison,EH
• 通讯作者: Harrison,EH

Avocado consumption enhances human postprandial provitamin A absorption and conversion from a novel high-β-carotene tomato sauce and from carrots.

• DOI: 10.3945/jn.113.187674
• 发表时间: 2014-08
• 期刊: The Journal of nutrition
• 作者: Kopec RE;Cooperstone JL;Schweiggert RM;Young GS;Harrison EH;Francis DM;Clinton SK;Schwartz SJ
• 通讯作者: Schwartz SJ

Synthesis of apo-13- and apo-15-lycopenoids, cleavage products of lycopene that are retinoic acid antagonists.

合成apo-13-和apo-15-番茄红素，番茄红素的裂解产物，是视黄酸拮抗剂。

• DOI: 10.1194/jlr.d073148
• 发表时间: 2017
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: Narayanasamy,Sureshbabu;Sun,Jian;Pavlovicz,RyanE;Eroglu,Abdulkerim;Rush,CassandraE;Sunkel,BenjaminD;Li,Chenglong;Harrison,EarlH;CurleyJr,RobertW
• 通讯作者: CurleyJr,RobertW