Revisiting the goldilocks phenomenon: folate and colorectal cancer risk.
Revisiting the goldilocks phenomenon: folate and colorectal cancer risk.
复制标题
重温金发姑娘现象：叶酸和结直肠癌风险。
DOI：
10.1038/ajg.2010.189
复制
发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Kim,SusanJ
中科院分区：
文献类型：
--
作者：
Mason,JoelB;Kim,SusanJ
叶酸的促癌作用可能与以下事实有关：肿瘤性结肠上皮细胞具有异常高的增殖率（33），因此对核苷酸的需求增加。因此，过量的叶酸可能会诱导加速增殖，因为维生素是从头胸苷合成（DNA合成的限速步骤）的重要辅助因子（34）。过量的叶酸可利用性从而消除胸苷酸作为细胞过度增殖的限制因素。事实上，叶酸不是维生素的天然存在形式，被食品和制药行业用于强化和补充也可能很重要。叶酸通常转化为维生素的天然生物形式（5-甲基四氢叶酸），因为它通过肠壁。然而，口服剂量小至200 μg可以饱和这种转换机制，导致循环叶酸（35）。有人担心这种氧化的、非取代形式的叶酸可能是有害的，因为它绕过某些调节节点，以四氢叶酸的形式进入叶酸代谢，四氢叶酸直接转化为5，10-亚甲基四氢叶酸，胸苷合成的必需辅因子。超过80%的维生素补充剂的经常使用者在血浆中可检测到未代谢的叶酸水平（36）。童话故事传达给孩子们的基本行为准则对我们和成年人一样有帮助。在这方面，也许我们应该从金发姑娘那里学到一个教训：叶酸类似于粥，最好是以一种“不太多......也不太少......但介于两者之间”的方式食用，因为这似乎是“恰到好处的量”。叶酸对癌症风险的影响，这个问题要复杂得多，因为对某些人来说安全的摄入量，甚至是化学预防的摄入量，可能会给其他人带来癌症促进的风险。老年个体更可能具有惰性瘤变病灶，因此，人们预测这些个体最有可能成为已报告的终点（26-29），并且没有观察到类似的肿瘤发生增加;然而，重要的是要注意，这些其他个体中没有一个具有科尔等人试验中提供的6-8年的延长随访。（20）、此外，在一项生态学研究中，我们观察到20世纪90年代中期美国和加拿大强制性强化谷物叶酸的全国结直肠癌诊断率每10万人增加约5例（30），这意味着美国每年增加15，000例病例。虽然生态学性质的研究有内在的弱点，必须考虑到在权衡科学证据，但该研究强调了一种可能性，即一般人群的某些部分所消耗的叶酸总量已经达到了可以促进癌症风险的水平。美国许多成年人摄入的叶酸量似乎在可能产生这种促癌作用的范围内。除了从饮食中的天然来源获得的叶酸外，还有大量的食品通过食品工业的自由裁量权或由于联邦政府强制强化面粉而用叶酸强化。此外，40%的59岁以上的美国成年人每周至少服用五次复合维生素（31）。此外，正是这些人最有可能寻求维生素的其他补充来源。吃一片复合维生素和一碗强化即食食品
The cancer-promoting effect of folate is likely related to the fact that a neoplastic colonic epithelium has an exceptionally high rate of proliferation (33) and therefore a heightened demand for nucleotides. Accelerated proliferation may therefore be induced by excess folate since the vitamin is an essential cofactor for de novo thymidine synthesis, a rate-limiting step for DNA synthesis (34). An overabundant availability of folate thereby removes thymidylate as a limiting factor in cellular hyperproliferation. The fact that folic acid, which is not a naturally occurring form of the vitamin, is used by food and pharmaceutical industries for fortification and supplementation may also be important. Folic acid is usually converted to a natural biological form of the vitamin (5-methyltetrahydrofolate) as it passes through the intestinal wall. However, oral doses as small as 200 μg can saturate this conversion mechanism, resulting in circulating folic acid (35). There is some concern that this oxidized, non-substituted form of folate might be detrimental since it bypasses certain regulatory nodes and enters folate metabolism in the form of tetrahydrofolate, which is converted directly to 5, 10-methylenetetrahydrofolate, the essential cofactor for thymidine synthesis. More than 80% of individuals who are regular users of vitamin supplements have detectable levels of unmetabolized folic acid in their plasma (36). The basic codes of conduct that fairy tales convey to our children are often just as helpful to us as adults. In this regard, perhaps we should learn a lesson from Goldilocks: that folate—like porridge—might best be consumed in a manner that is “not too great… and not too little… but somewhere in between,” because that seems to be “just the right amount.” The issue is considerably more complex for folate in regard to its effects on cancer risk, since a level of intake that is safe, or even chemopreventive for some, might present a risk of cancer promotion to others. Older individuals are more likely to harbor indolent foci of neoplasia, and it is these individuals who one would therefore predict would be most an end point have been reported (26–29), and none has observed a similar increase in tumorigenesis; however, it is important to note that none of these others has had the extended follow-up over 6–8 years that was provided for in the trial of Cole et al.(20). Moreover, in an ecological study, we observed an increase of about 5 cases per 100,000 individuals in the nationwide rates of colorectal cancer diagnoses in conjunction with the institution of mandatory folic acid fortification of cereal grains in both the United States and Canada in the mid-1990s (30), which translates to 15,000 additional cases in the United States each year. Although studies of an ecological nature have inherent weaknesses that must be taken into account in weighing the scientific evidence, the study nevertheless underscores the possibility that the total amount of folate consumed by some segments of the general population has achieved a level that can promote cancer risk. The quantity of folate consumed by many adults in the United States seems to fall within a range that might produce this cancer-promoting effect. In addition to the folate obtained from natural sources in the diet, there are a plethora of foodstuffs that are fortified with folic acid either by discretion of the food industry or because of federally mandated fortification of flour. Furthermore, 40% of US adults over the age of 59 consume a multivitamin at least five times per week (31). Moreover, it is these individuals who are the most likely to seek out other supplemental sources of the vitamin. By consuming a multivitamin and a bowl of fortified ready-to-eat …