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

类维生素a与其他营养物质以及某些激素和化学预防和/或化学治疗剂之间的相互作用仍有待澄清。这些相互作用与各种致癌过程之间的关系就更不清楚了。我们在体内和体外进行了一些补充性的研究，以研究类维甲酸-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学的数学/区室模型来描述类维甲酸的代谢和各种类维甲酸在许多组织中的相互作用。例如，我们之前的工作表明，合成类维甲酸4HPR似乎会干扰眼睛和前列腺以及其他一些组织对维生素A的正常摄取和/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。相反，全反式维甲酸的施用与类维甲酸动力学中类似类型的扰动无关。为了验证从体内模型中得出的假设，并更详细地研究所涉及的机制，我们筛选并随后开发了一些体外系统，专门设计来尽可能地模拟我们在体内观察到的生理反应。到目前为止，我们已经在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中进行了研究。利用我们实验室开发的高效液相色谱法和光电二极管阵列分析方法，我们研究了这些系统中一些天然的和给药的类维生素a和药物的动力学。在其他发现中，我们已经证明了在这些系统中存在类维甲酸酯化活性以及不同类维甲酸的摄取和代谢。我们目前正在描述这种活性以及相关的分子事件，如类视黄酮结合蛋白和核类视黄酮受体的表达，是如何被各种类视黄酮、营养、药物和激素治疗所改变的。在一个合作项目中，我们开发了一种方法，可以同时监测人类血浆样本中的天然维甲酸和给药维甲酸，这些样本将在临床研究试验中使用4HPR作为化学预防剂收集。在另一个合作项目中，我们正在比较几种不同的类维甲酸治疗方法（包括4HPR和这种类维甲酸的几种新变体）对天然类维甲酸代谢和相关分子事件的影响，这些组织包括眼睛、前列腺、肝脏、肾脏和结肠。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大量类胡萝卜素、类维甲酸和生育酚的方法。我们目前正在使用这种方法来研究在p-53缺陷转基因小鼠模型中补充β -胡萝卜素和α -生育酚如何影响许多选定组织中的类视黄醇代谢。-化疗，营养，药理学，调节，类维生素a，

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,