Low-Dose Methotrexate Inhibits Methionine S-Adenosyltransferase In Vitro and In Vivo

Wang, Yicheng; Chiang, En‐Pei Isabel

doi:10.2119/molmed.2011.00048

Cited by 53 publications

(55 citation statements)

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“…In the current study (Fig. 3), there was a moderate decrease of hepatic mRNA expression for Mat2a (33.5%) in mice on the high-fructose diet, thus, this diet might lead to low delivery of S -adenosylmethionine from the liver to plasma and tissues, and increase the susceptibility to liver injury and/or promote the progression of existing liver diseases (Wang and Chiang, 2012). …”

Section: Discussionmentioning

confidence: 56%

“…As3mt is the arsenic methyltransferase that converts inorganic arsenic to the methylated metabolite (Dodmane et al , 2013), and down-regulation of this enzyme in mice on the western and atherogenic diet might alter the disposition and retention of arsenic in arsenate-treated mice. Methionine adenosyltransferase (Mat) catalyzes the synthesis of the major methyl donor S -adenosylmethionine in mammals, and increase risk of liver pathogeneses has been reported in extreme Mat deficiency in humans and mouse models (Wang and Chiang, 2012). In the current study (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Effect of nine diets on mRNAs of phase-II conjugation enzymes in livers of mice

et al. 2016

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Phase-II enzymes are important in metabolizing many xenobiotics including prescription drugs and chemical carcinogens. Whereas it is known that diet can alter the expression of phase-II conjugation enzymes, the previous studies are limited in using only two or three diets and examining only a few enzymes.Adult male C57BL6 mice were fed one of 9 diets for 3 weeks. Of the 87 genes encoding major hepatic phase-II enzymes, approximately one-half (43) were altered by at least one diet. Diet restriction altered the hepatic expression of the most genes encoding phase-II enzymes (27), followed by lab chow (15), atherogenic diet (13), high-fat diet (10), western diet (7), high-fructose diet (5), and essential fatty acid-deficient diet (3), whereas the low n-3 fatty acid diet had no effect on the hepatic expression of these phase-II enzymes.This comprehensive study provides detailed information on which conjugation enzymes are changed by these diets, and these data can be used to further investigate the mechanism for these changes in messenger RNAs, and whether these changes result in alterations in enzyme activity and drug action.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Effect of nine diets on mRNAs of phase-II conjugation enzymes in livers of mice

et al. 2016

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“…Blood and tissue samples were stored at −80°C for analysis of homocysteine, S ‐adenosylmethionine (adoMet), S ‐adenosylhomocysteine (adoHcy), and adenosine. Liver tissues were extracted with 0.4 M perchloric acid and supernatants were filtered just prior to HPLC analysis . Plasma total (unbound and bound) homocysteine, was measured by HPLC with fluorometric detection …”

Section: Methodsmentioning

confidence: 99%

“…Liver tissues were extracted with 0.4 M perchloric acid and supernatants were filtered just prior to HPLC analysis. [30][31][32] Plasma total (unbound and bound) homocysteine, 33 was measured by HPLC with fluorometric detection. 34…”

Section: Determination Of S-adenosylmethionine Sadenosylhomocysteinementioning

confidence: 99%

A novel role of the tumor suppressor GNMT in cellular defense against DNA damage

Wang

Wei

Lin

et al. 2013

Intl Journal of Cancer

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Glycine N-methyltransferase (GNMT) is a folate binding protein commonly diminished in human hepatoma yet its role in tumor development remains to be established. GNMT binds to methylfolate but is also inhibited by it; how such interactions affect human carcinogenesis is unclear. We postulated that GNMT plays a role in folate-dependent methyl group homeostasis and helps maintain genome integrity by promoting nucleotide biosynthesis and DNA repair. To test the hypothesis, GNMT was over-expressed in GNMT-null cell lines cultured in conditions of folate abundance or restriction. The partitioning of folate dependent 1-carbon groups was investigated using stable isotopic tracers and GC/MS. DNA damage was assessed as uracil content in cell models, as well as in Gnmt wildtype (Gnmt 1/1 ), heterozygote (Gnmt) and knockout (Gnmt 2/2 ) mice under folate deplete, replete, or supplementation conditions. Our study demonstrated that GMMT 1) supports methylene-folate dependent pyrimidine synthesis; 2) supports formylfolate dependent purine syntheses; 3) minimizes uracil incorporation into DNA when cells and animals were exposed to folate depletion; 4) translocates into nuclei during prolonged folate depletion.In conclusion, loss of GNMT impairs nucleotide biosynthesis. Over-expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo. To our best knowledge, the role of GNMT in folate dependent 1-carbon transfer in nucleotide biosynthesis has never been investigated. The present study gives new insights into the underlying mechanism by which GNMT can participate in tumor prevention/suppression in humans.

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“…12 There is a recent report that MTX can inhibit the expression of methionine S-adenosyltransferase-1 and -2 genes. 29 This would also reduce SAM levels by blocking the conversion of methionine to SAM.…”

Section: Treatment Indicationsmentioning

confidence: 99%

Methotrexate and Pralatrexate

Wood

2015

Dermatologic Clinics

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This article reviews methotrexate and the more potent, related compound, pralatrexate, for the treatment of cutaneous T-cell lymphomas, including mycosis fungoides, Sézary syndrome, and CD30+ lymphoproliferative disorders. Although these folate antagonists are traditionally viewed as antiproliferative cell cycle inhibitors, it is recognized that they inhibit DNA methylation, providing a rationale for their use as epigenetic regulators and cell proliferation inhibitors. The underlying mechanisms are outlined, key supporting data presented, followed by brief mention of recent mathematical modeling supporting the general superiority of combination therapy. Several novel examples involving folate antagonists are proposed.

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Low-Dose Methotrexate Inhibits Methionine S-Adenosyltransferase In Vitro and In Vivo

Cited by 53 publications

References 56 publications

Effect of nine diets on mRNAs of phase-II conjugation enzymes in livers of mice

Effect of nine diets on mRNAs of phase-II conjugation enzymes in livers of mice

A novel role of the tumor suppressor GNMT in cellular defense against DNA damage

Methotrexate and Pralatrexate

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