Psoralens and melanoma

 描述(申请人提供)：皮肤黑色素瘤的发病率一直在增加。我们最近发现，摄取柑橘类水果，特别是葡萄柚，与患黑色素瘤的风险增加有关，并认为柑橘类水果中的补骨脂素可能与这种联系有关。口服8-甲氧基补骨脂素(8-MOP；美索沙林)结合紫外线-A辐射(补骨脂素和UVA光[PUVA]疗法)用于治疗皮肤病，并被发现与黑色素瘤发病率增加有关。补骨脂素是一组天然存在于水果和蔬菜中的线性呋喃香豆素(呋喃香豆素)，具有潜在的光毒性和光致癌作用；它们嵌入DNA并通过光化学诱导突变。我们饮食中存在的呋喃香豆素水平，虽然通常远低于会导致明显急性光毒性的水平，但确实会引起与药物相关的相互作用，即所谓的“葡萄柚效应”。此外，补骨脂素在人体内的代谢解毒还没有有效的途径。因此，补骨脂素的低水平可能会出现在我们的皮肤中，等待合适的光子相互作用，从而产生突变损害，可能导致黑色素瘤或其他皮肤癌。在美国，柑橘类水果的消费量大幅增加。然而，缺乏关于饮食补骨脂素摄入与黑色素瘤风险相关的流行病学数据，因为饮食补骨脂素的食物组成数据库不可用。缺乏关于人类血液和尿补骨脂素水平的数据。因此，在这项建议中，我们计划利用在大型队列研究中收集的现有饮食数据(其中发现柑橘水果摄入量与黑色素瘤风险之间存在正相关)，并建议通过直接评估补骨脂素含量丰富的食物中的几种常见补骨脂素来构建饮食补骨脂素食物成分数据库，包括柑橘类水果食品，并通过至少1,000例黑色素瘤病例评估饮食补骨脂素摄入量与黑色素瘤风险的关系。我们还建议进行一项试点研究，以调查我们是否可以在大型队列研究的归档血液和尿样中检测到这些补骨脂素，并评估实验室的变异性、由于加工延迟而导致的稳定性以及血和尿补骨脂素的人内变异性。我们处于独特的地位，可以最有效地解决这些假设。这项研究的结果将为未来的研究铺平道路，这些研究将利用这些发现，并导致对血浆或尿补骨脂素水平的研究，以揭示自然发生的补骨脂素在癌症发生中的作用。由于预防癌症的饮食指南鼓励食用水果和蔬菜，澄清天然补骨脂素对致癌的影响具有公共卫生影响，正如我们通过葡萄柚效应的发现所经历的那样。

 DESCRIPTION (provided by applicant): Incidence of cutaneous melanoma has been increasing. We recently found that intake of citrus fruits, especially grapefruit, was associated with increased risk of developing melanoma and believe that psoralens in citrus fruits may be responsible for the association. An oral 8-methoxy psoralen (8-MOP; methoxsalen) in combination with ultraviolet-A radiation (Psoralen and UVA Light [PUVA] therapy) is used to treat skin disorders and found to be associated with increased incidence of melanoma. Psoralens are a group of naturally occurring linear furocoumarins (furanocoumarins) in fruits and vegetables and are potentially phototoxic and photocarcinogenic; they intercalate DNA and photochemically induce mutations. The levels of furocoumarins present in our diets, while normally well below levels that would cause evident acute phototoxicity, do cause pharmacologically relevant drug interactions, known as the `grapefruit effect'. Furthermore, there are no efficient routes for the metabolic detoxification of psoralens in humans. Consequently, low levels of psoralens, which are not completely excreted, may occur in our skin awaiting suitable photon interactions to create mutational lesions potentially resulting in melanoma or other skin cancers. Citrus fruit consumption has increased substantially in the US. However, there is a lack of epidemiological data on dietary psoralen intake in relation to melanoma risk because food composition database for dietary psoralens are not available. Data are lacking on blood and urine psoralen levels in humans. Therefore, in this proposal, we plan to capitalize on existing dietary data collected in large cohort studies (where the positive association between citrus fruit intake and melanoma risk was found) and propose to construct a food composition database on dietary psoralens through direct assessment of several common psoralens in psoralen-rich foods including citrus fruit items and to evaluate dietary psoralen intake in relation to melanoma risk with at least 1,000 melanoma cases. We also propose to conduct a pilot study to investigate whether we can detect these psoralens in archived blood and urine samples of large cohort studies and to assess laboratory variability, stability due to delays in processing, and within-person variability of the blood and urinary psoralens. We are uniquely positioned to most efficiently address the hypotheses. The results of the investigation will pave the way for future studies that will capitalize on these findings and cn lead to studies of plasma or urine psoralen levels to unveil the roles of naturally occurring psoralens in carcinogenesis. Because dietary guidelines for cancer prevention encourage consumption of fruits and vegetables, clarification of the effect of naturally occurring psoralens on carcinogenesis has public health implications as we have experienced through the findings of `grapefruit effect'.