MODELING OF RETINOID-NUTRIENT-DRUG INTERACTIONS: COMPLIMENTARY <I>IN VIVO</I> AND

视黄醇-营养素-药物相互作用的建模：补充<I>体内</I>和

• 批准号: 6289055
• 负责人: KEVIN C LEWIS
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289055
• 关键词: chemoprevention; computer simulation; human tissue; laboratory rat; nutrient bioavailability; nutrient drug interaction; nutrition aspect of cancer; nutrition related tag; pharmacokinetics; prostate; protein isoforms; retinoate; retinoid binding proteins; retinoids; tissue /cell culture; vitamin analog; vitamin metabolism

The interactions among retinoids and other nutrients as well as certain hormones and chemopreventive and/or chemotherapeutic agents remain to be clarified. The relationship between these interactions and various carcinogenic processes are even less well characterized. We have carried out a number of complementary in vivo and in vitro studies to examine the mechanisms involved in retinoid-nutrient-drug interactions and their role in cancer. Based on our in vivo studies, we have developed physiologically based, mathematical/compartmental models to describe the metabolism of retinoids and various retinoid interactions in a number of tissues. For example, our previous work has indicated that the synthetic retinoid 4HPR appears to interfere with normal uptake and/or metabolism of vitamin A in the eyes and prostate as well as a number of other tissues examined. Our findings in the eyes have provided a possible explanation for the visual disturbances often observed in human trials using 4HPR. In contrast, administration of all-trans retinoic acid was not associated with similar types of perturbations in retinoid kinetics. To test the hypotheses derived from our in vivo models and to study the mechanisms involved in greater detail, we have screened and subsequently developed a number of in vitro systems specifically designed to simulate as closely as possible, the physiological responses we have observed in vivo. Thus far, we have carried out studies in a novel tissue culture system for human retinal pigment epithelium and a modified human prostate carcinoma cell line. Using HPLC and photodiode array analytical methods developed in our laboratory, we have studied the dynamics of a number of native and administered retinoids and drugs in these systems. Among other findings, we have demonstrated the presence of retinoid esterification activity in these systems as well as uptake and metabolism of different retinoids. We are presently characterizing how this activity as well related molecular events, such as expression of retinoid-binding proteins and nuclear retinoid receptors, are altered by various retinoid, nutrient, drug and hormonal treatments. For a collaborative project, we have developed methodology to simultaneously monitor native and administered retinoids in human plasma samples to be collected in a clinical study trial using 4HPR as a chemopreventive agent. In another collaborative project we are comparing the effects of several different retinoid treatments including 4HPR and several new variants of this retinoid, on metabolism of native retinoids and related molecular events, in a number of tissues including the eyes, prostate, liver, kidneys, and colon. For an additional collaborative study, we have developed methodology to isolate and monitor a number of carotenoid, retinoid, and tocopherol species in plasma and tissues. We are presently using this methodology to investigate how beta-carotene and alpha-tocopherol supplementation in a p-53 deficient transgenic mouse model affect retinoid metabolism in a number of selected tissues. - chemotherapy, nutrition, Pharmacology, regulation, retinoids,

维甲酸和其他营养素之间的相互作用以及某些激素和化学预防和/或化疗药物之间的相互作用仍有待阐明。这些相互作用和各种致癌过程之间的关系甚至还没有得到很好的描述。我们在体内和体外进行了一些补充研究，以考察维甲酸-营养-药物相互作用的机制及其在癌症中的作用。基于我们的体内研究，我们开发了基于生理的、数学的/隔室模型来描述维甲酸的代谢和在许多组织中的各种维甲酸相互作用。例如，我们之前的工作表明，合成的维甲酸4HPR似乎干扰眼睛和前列腺以及其他一些组织对维生素A的正常吸收和/或代谢。我们在眼睛中的发现为在使用4HPR的人体试验中经常观察到的视觉障碍提供了可能的解释。相比之下，服用全反式维甲酸与维甲酸动力学中类似类型的扰动无关。为了测试我们的体内模型得出的假说并更详细地研究涉及的机制，我们筛选并随后开发了一些体外系统，这些系统专门设计来尽可能接近地模拟我们在体内观察到的生理反应。到目前为止，我们已经开展了一种新的人视网膜色素上皮组织培养系统和一种改良的人前列腺癌细胞系的研究。利用我们实验室开发的高效液相色谱和光电二极管阵列分析方法，我们研究了一些天然和给药的维甲酸和药物在这些系统中的动力学。在其他发现中，我们已经证明了在这些系统中存在类维A酸酯化活性，以及不同类维A酸的吸收和代谢。我们目前正在研究这种活性以及相关的分子事件，如维甲酸结合蛋白和核维甲酸受体的表达，是如何通过各种维甲酸、营养、药物和激素治疗而改变的。在一个合作项目中，我们开发了一种方法，以同时监测人类血浆样本中天然和给予维甲酸的样本，该样本将在临床研究试验中收集，使用4HPR作为化学预防性药物。在另一个合作项目中，我们正在比较几种不同的维甲酸治疗方法，包括4HPR和这种维甲酸的几个新变种，在包括眼睛、前列腺、肝脏、肾脏和结肠在内的许多组织中，对天然维甲酸代谢和相关分子事件的影响。在另一项合作研究中，我们开发了分离和监测血浆和组织中的一些类胡萝卜素、类维A酸和生育酚的方法。我们目前正在使用这种方法来研究在p-53基因缺陷的转基因小鼠模型中补充β-胡萝卜素和α-生育酚如何影响一些选定组织中的维甲酸代谢。-化疗、营养、药理、调节、维甲酸、