Research Center, CHU Sainte-Justine, Montreal, QC, Canada.
Curr Genomics. 2010 Dec;11(8):578-83. doi: 10.2174/138920210793360925.
Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF). THF is needed for the action of folate-dependent enzymes and is thus essential for DNA synthesis and methylation. The importance of this reaction is demonstrated by the effectiveness of antifolate medications used to treat cancer by inhibiting DHFR, thereby depleting THF and slowing DNA synthesis and cell proliferation. Due to the pivotal role that DHFR plays in folate metabolism and cancer treatment, changes in the level of DHFR expression can affect susceptibility to a variety of diseases dependent on folate status such as spina bifida and cancer. Likewise, variability in DHFR expression can affect sensitivity to anti-cancer drugs such as the folate antagonist methotrexate. Alterations in DHFR expression can be due to polymorphisms in the DHFR gene. Several variations have recently been described in DHFR, including promoter polymorphisms, the 19-bp deletion allele and variations in 3'UTR. These polymorphisms seem to be functional, affecting mRNA levels through various interesting mechanisms, including regulation through RNA interference. Several groups have assessed the association of these polymorphisms with folate levels, risk of cancer and spina bifida as well as the outcome of diseases treated with MTX. The latter may lead to different treatment schedules, improving treatment efficacy and/or allowing for a reduction in drug side effects. This review will summarize present knowledge regarding the predictive potential of DHFR polymorphisms in disease and treatment.
二氢叶酸还原酶（DHFR）催化二氢叶酸还原为四氢叶酸（THF）。THF 是叶酸依赖性酶发挥作用所必需的，因此对 DNA 合成和甲基化至关重要。抗叶酸药物通过抑制 DHFR 来治疗癌症的有效性证明了这一反应的重要性，从而耗尽 THF，减缓 DNA 合成和细胞增殖。由于 DHFR 在叶酸代谢和癌症治疗中起着关键作用，DHFR 表达水平的变化可能会影响对各种依赖叶酸状态的疾病的易感性，如脊柱裂和癌症。同样，DHFR 表达的可变性也会影响对癌症药物如叶酸拮抗剂甲氨蝶呤的敏感性。DHFR 表达的改变可能是由于 DHFR 基因的多态性。最近已经描述了 DHFR 的几种变体，包括启动子多态性、19bp 缺失等位基因和 3'UTR 的变异。这些多态性似乎是功能性的，通过各种有趣的机制影响 mRNA 水平，包括通过 RNA 干扰进行调节。一些研究小组已经评估了这些多态性与叶酸水平、癌症和脊柱裂风险以及 MTX 治疗疾病的结果之间的关联。这可能导致不同的治疗方案，提高治疗效果和/或减少药物的副作用。这篇综述将总结目前关于 DHFR 多态性在疾病和治疗中的预测潜力的知识。
