Altered expression of methylenetetrahydrofolate reductase modifies response to methotrexate in mice

被引：19

作者：

Celtikci, Basak ^{[1
,2
]}

Leclerc, Daniel ^{[1
,2
]}

Lawrance, Andrea K. ^{[1
,2
]}

Deng, Liyuan ^{[1
,2
]}

Friedman, Hana C. ^{[3
,4
]}

Krupenko, Natalia I. ^{[5
]}

Krupenko, Sergey A. ^{[5
]}

Melnyk, Stepan ^{[6
]}

James, S. Jill ^{[6
]}

Peterson, Alan C. ^{[3
,4
]}

Rozen, Rima ^{[1
,2
]}

机构：

[1] McGill Univ, Montreal Childrens Hosp, Res Inst, Ctr Hlth,Dept Human Genet, Montreal, PQ H3Z 2Z3, Canada

[2] McGill Univ, Montreal Childrens Hosp, Res Inst, Ctr Hlth,Dept Pediat, Montreal, PQ H3Z 2Z3, Canada

[3] McGill Univ, Ctr Hlth, Dept Neurol, Montreal, PQ H3Z 2Z3, Canada

[4] McGill Univ, Ctr Hlth, Dept Neurosurg, Montreal, PQ H3Z 2Z3, Canada

[5] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA

[6] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Dept Pediat, Res Inst, Little Rock, AR 72205 USA

来源：

PHARMACOGENETICS AND GENOMICS | 2008年 / 18卷 / 07期

关键词：

hematocrit hemoglobin; homocysteine; methotrexate; methylenetetrahydrofolate reductase; polymorphism; red blood cells; thymidylate;

D O I：

10.1097/FPC.0b013e32830058aa

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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(-1-) 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. Pharmacogenetics and Genomics 18:577-589 (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

引用

页码：577 / 589

页数：13

共 44 条

[1] A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells [J].