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首页> 外文期刊>Pharmacogenetics and genomics >Altered expression of methylenetetrahydrofolate reductase modifies response to methotrexate in mice.
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Altered expression of methylenetetrahydrofolate reductase modifies response to methotrexate in mice.

机译：亚甲基四氢叶酸还原酶表达的改变会改变小鼠对甲氨蝶呤的反应。

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OBJECTIVE: Folates provide one-carbon units for nucleotide synthesis and methylation reactions. A common polymorphism (677C-->T) in methylenetetrahydrofolate reductase (MTHFR) encodes an enzyme with reduced activity. Response to the antifolate methotrexate (MTX) may be modified in 677TT individuals because MTHFR converts nonmethylated folates, used for thymidine and purine synthesis, to 5-methyltetrahydrofolate, used in homocysteine remethylation to methionine. To study potential interactions between MTHFR activity and MTX, we examined the impact of decreased and increased MTHFR expression on MTX response in mice. METHODS: Mthfr-deficient (Mthfr and Mthfr) and wild-type (Mthfr) mice were injected with MTX or saline and assessed for hematological parameters (hematocrit, hemoglobin, red, and white blood cell numbers), plasma homocysteine, nephrotoxicity, hepatotoxicity, and splenic 2'-deoxyuridine 5'-triphosphate/2'-deoxythymidine 5'-triphosphate ratios. MTHFR-overexpressing transgenic mice (MTHFR-Tg) were generated, metabolites and folate distributions were measured, and response to MTX was assessed. RESULTS: MTX-treated Mthfr and Mthfr mice displayed hyperhomocysteinemia and decreased hematocrit, hemoglobin, and red blood cell numbers compared with wild-type animals. Mthfr mice also showed increased nephrotoxicity and hepatotoxicity. MTHFR-Tg mice were generated and confirmed to have increased levels of MTHFR with altered distributions of folate and thiols in a tissue-specific manner. After MTX treatment, MTHFR-Tg mice exhibited the same decreases in hematological parameters as Mthfr-deficient mice, and significantly decreased thymidine synthesis (higher 2'-deoxyuridine 5'-triphosphate/2'-deoxythymidine 5'-triphosphate ratios) compared with wild-type mice, but they were protected from MTX-induced hyperhomocysteinemia. CONCLUSION: Underexpression and overexpression of Mthfr/MTHFR increase MTX-induced myelosuppression but have distinct effects on plasma homocysteine and nephrotoxicity. Pharmacogenetic analysis of polymorphisms in folate-dependent enzymes may be useful in optimization of MTX therapy.
机译：目的：叶酸为核苷酸合成和甲基化反应提供一个碳原子单元。亚甲基四氢叶酸还原酶（MTHFR）中常见的多态性（677C→T）编码一种活性降低的酶。 677TT个体对抗叶酸甲氨蝶呤（MTX）的反应可能会有所改变，因为MTHFR将用于胸腺嘧啶和嘌呤合成的非甲基化叶酸转化为用于高半胱氨酸再甲基化为蛋氨酸的5-甲基四氢叶酸。为了研究MTHFR活性和MTX之间的潜在相互作用，我们检查了MTHFR表达下降和增加对小鼠MTX反应的影响。方法：向Mthfr缺陷型（Mthfr和Mthfr）和野生型（Mthfr）小鼠注射MTX或盐水，并评估其血液学参数（血细胞比容，血红蛋白，红细胞和白细胞数），血浆高半胱氨酸，肾毒性，肝毒性，和脾脏的2'-脱氧尿苷5'-三磷酸/ 2'-脱氧胸苷5'-三磷酸比例。产生了过表达MTHFR的转基因小鼠（MTHFR-Tg），测量了代谢物和叶酸的分布，并评估了对MTX的反应。结果：与野生型动物相比，MTX处理的​​Mthfr和Mthfr小鼠表现出高同型半胱氨酸血症，血细胞比容，血红蛋白和红细胞数量减少。 Mthfr小鼠还显示出增加的肾毒性和肝毒性。产生了MTHFR-Tg小鼠，并确认其具有以组织特异性方式改变的叶酸和硫醇分布，并增加了MTHFR水平。与野生型相比，MTX处理后，MTHFR-Tg小鼠的血液学参数降低与Mthfr缺陷型小鼠相同，并且胸腺嘧啶核苷的合成显着降低（较高的2'-脱氧尿苷5'-三磷酸/ 2'-脱氧胸苷5'-三磷酸比例）型小鼠，但它们受到MTX诱导的高同型半胱氨酸血症的保护。结论：Mthfr / MTHFR的过表达和过表达会增加MTX诱导的骨髓抑制，但对血浆同型半胱氨酸和肾毒性有明显的影响。叶酸依赖性酶中多态性的药物遗传学分析可能对优化MTX治疗有用。

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