METABOLIC PROFILE OF TAMOXIFEN WITH PHARMACOGENETIC PREDICTORS & CLINICAL EFFECT

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。他莫昔芬是一种选择性雌激素受体调节剂(SERM)，全世界许多女性都可以使用。他莫昔芬用于治疗转移性乳腺癌，更常见的是作为原发性乳腺癌的辅助治疗。此外，该药物最近已被FDA批准用于降低乳腺癌高危女性的乳腺癌发病率。众所周知，接受三苯氧胺治疗的女性还会有其他好处，包括潜在的骨矿密度和血脂水平的改善。凝血因子图谱的变化也被注意到。三苯氧胺治疗的副作用包括潮热和子宫内膜癌发病率的小幅增加。潮热的病理生理学还不是很清楚。由于下丘脑体温调节设定值的全球变化。然后，由于触发，女性可能会出现潮热。然而，雌激素、其他激素和神经递质的减少之间的关系却知之甚少。此外，女性易患潮热的因素也只是部分确定。他莫昔芬通过细胞色素P450酶系统在肝脏中广泛代谢。已知药物代谢酶基因多态性与药物的不同反应有关。这项试验的目的是将他莫昔芬不同的遗传代谢特征与药物遗传学预测因素和临床效果相关联，包括血脂浓度、骨密度、骨转换代谢物、凝血因子和潮热。我们的假设是，他莫昔芬代谢物不良的女性将体验到较少的益处和潜在的较少毒性。我们将评估他莫昔芬治疗带来的血脂谱、骨密度、骨转换代谢产物和凝血因子的变化，并将研究结果与他莫昔芬独特的遗传代谢谱和参与他莫昔芬作用的重要候选基因的基因类型相关联。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tamoxifen is a selective estrogen receptor modulator (SERM) prescribed to many women worldwide. Tamoxifen is used for the treatment of metastatic breast cancer and, more often, as adjuvant therapy for primary breast cancer. In addition, the drug has been recently approved by the FDA for reduction of breast cancer incidence in women whoa re at a high risk for developing the disease. It is known that women who are treated with tamoxifen experience other benefits that include potential improvement in bone mineral density and lipid profile. Changes in coagulation factor profile are also noted. Adverse effects of Tamoxifen therapy include hot flashes and a small increase in the incidence of endometrial cancer. The pathophysiology of hot flashes is not well understood. Due to a global change in the thermoregulatory set point in the hypothalamus. Then, as a result of a trigger, a woman may suffer hot flashes. However, the relationship between a decrease in estrogen, other hormones, and neurotransmitters, is poorly understood. In addition, factors that predispose individual women to hot flashes are only partially established. Tamoxifen is extensively metabolized by the liver via cytochrome P450 enzyme system. It is known that genetic polymorphisms in drug metabolizing enzymes are associated with different responses to drugs. The purpose of this trial is to correlate genetically distinct metabolic profiles of tamoxifen with pharmacogenetic predictors and clinical effects that include lipid concentration, bone mineral density, bone turnover metabolites, coagulation factors, and hot flashes. Our hypothesis is that women who are poor tamoxifen metabolizers will experience less benefit and potentially less toxicity. We will evaluate changes in lipid profile, bone mineral density, and bone turnover metabolites, and coagulation factors brought about by tamoxifen therapy, and correlate the findings with genetically distinct metabolic profiles of tamoxifen and genotypes for important candidate genes involved in the action of tamoxifen.