Department of Biochemistry, University of Otago, Dunedin 9054, New Zealand.
Pharmacogenomics. 2011 Oct;12(10):1449-63. doi: 10.2217/pgs.11.86.
Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis and is frequently used in the management of other forms of inflammatory arthritis. It is currently challenging to predict which patients will achieve adequate disease control and which patients will develop adverse effects while taking MTX. As an analog of dihydrofolic acid, MTX enters cells through the reduced folate carrier-1 protein, and is polyglutamated. MTX polyglutamates inhibit key enzymes in the folate pathway to produce an anti-inflammatory effect. It has been suggested that genetic polymorphisms in the folate pathway may influence intracellular folate and MTX polyglutamates pools, and thus MTX response. However, studies to identify genetic predictors have yielded inconclusive results. Nonreplication across studies has been attributed to insufficient statistical power as well as pharmacological and clinical confounders. Prospective studies, standardizing the definitions of response and toxicity, and application of genome-wide approaches may advance the search for genetic predictors of MTX response.
甲氨蝶呤（MTX）是类风湿关节炎的一线治疗药物，常用于治疗其他形式的炎症性关节炎。目前，预测哪些患者将获得充分的疾病控制，哪些患者在服用 MTX 时会出现不良反应具有挑战性。作为二氢叶酸的类似物，MTX 通过还原叶酸载体-1 蛋白进入细胞，并聚谷氨酸化。MTX 聚谷氨酸抑制叶酸途径中的关键酶，产生抗炎作用。有人认为，叶酸途径中的遗传多态性可能会影响细胞内叶酸和 MTX 聚谷氨酸池，从而影响 MTX 的反应。然而，鉴定遗传预测因子的研究并未得出明确的结果。研究结果无法重复归因于统计效力不足以及药理学和临床混杂因素。前瞻性研究，标准化反应和毒性的定义，以及全基因组方法的应用，可能会促进寻找 MTX 反应的遗传预测因子。
