{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T04:54:07Z","timestamp":1779080047337,"version":"3.51.4"},"reference-count":53,"publisher":"Elsevier BV","issue":"1","license":[{"start":{"date-parts":[[2004,1,1]],"date-time":"2004-01-01T00:00:00Z","timestamp":1072915200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,2,11]],"date-time":"2023-02-11T00:00:00Z","timestamp":1676073600000},"content-version":"vor","delay-in-days":6981,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Nutrition"],"published-print":{"date-parts":[[2004,1]]},"DOI":"10.1093\/jn\/134.1.48","type":"journal-article","created":{"date-parts":[[2018,1,22]],"date-time":"2018-01-22T06:22:59Z","timestamp":1516602179000},"page":"48-56","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":137,"title":["Methylenetetrahydrofolate Reductase C677T Polymorphism, Folic Acid and Riboflavin Are Important Determinants of Genome Stability in Cultured Human Lymphocytes"],"prefix":"10.1016","volume":"134","author":[{"given":"Michiyo","family":"Kimura","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keizo","family":"Umegaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuru","family":"Higuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Fenech","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1093\/jn\/134.1.48_bib1","unstructured":"Selhub, J. & Rosenberg, I. H. (1996) Folic acid. In: Present Knowledge in Nutrition (Ziegler, E. E. & Filer, L. J., eds.), 7th ed., pp. 206\u2013219. ILSI Press, Washington, D.C."},{"key":"10.1093\/jn\/134.1.48_bib2","doi-asserted-by":"crossref","first-page":"2413S","DOI":"10.1093\/jn\/132.8.2413S","article-title":"Folate status: effects on pathways of colorectal carcinogenesis","volume":"132","author":"Choi","year":"2002","journal-title":"J. Nutr"},{"key":"10.1093\/jn\/134.1.48_bib3","first-page":"56","article-title":"The role of folic acid and vitamin B12 in genomic stability of human cells","volume":"475","author":"Fenech","year":"2001","journal-title":"Mutat. Res"},{"key":"10.1093\/jn\/134.1.48_bib4","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/nrc886","article-title":"Are vitamin and mineral deficiencies a major cancer risk?","volume":"2","author":"Ames","year":"2002","journal-title":"Nature Rev. Cancer"},{"key":"10.1093\/jn\/134.1.48_bib5","unstructured":"Rivlin, R. S. (1996) Riboflavin. In: Present Knowledge in Nutrition (Ziegler, E. E. & Filer, L. J., eds.), 7th ed., pp. 206\u2013219. ILSI Press, Washington, D.C."},{"issue":"8","key":"10.1093\/jn\/134.1.48_bib6","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1093\/clinchem\/46.8.1065","article-title":"Riboflavin as a determinant of plasma total homocysteine: effect of modification by the methylenetetrahydrofolate reductase C677T polymorphism","volume":"46","author":"Hustad","year":"2000","journal-title":"Clin. Chem"},{"key":"10.1093\/jn\/134.1.48_bib7","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/S0950-3536(05)80216-1","article-title":"DNA damage in folate deficiency","volume":"8","author":"Blount","year":"1995","journal-title":"Baillere's Clin. Haematol"},{"key":"10.1093\/jn\/134.1.48_bib8","doi-asserted-by":"crossref","first-page":"3290","DOI":"10.1073\/pnas.94.7.3290","article-title":"Folate deficiency causes uracil midincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage","volume":"94","author":"Blount","year":"1997","journal-title":"Proc Natl. Acad. Sci. U.S.A"},{"key":"10.1093\/jn\/134.1.48_bib9","doi-asserted-by":"crossref","first-page":"12810","DOI":"10.1073\/pnas.96.22.12810","article-title":"Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukaemia in adults","volume":"96","author":"Skibola","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"issue":"10","key":"10.1093\/jn\/134.1.48_bib10","doi-asserted-by":"crossref","first-page":"3205","DOI":"10.1182\/blood.V97.10.3205","article-title":"Association between polymorphisms of folate- and methionine-metabolising enzymes and susceptibility to malignant lymphoma","volume":"97","author":"Matsuo","year":"2001","journal-title":"Blood"},{"key":"10.1093\/jn\/134.1.48_bib11","doi-asserted-by":"crossref","first-page":"2350S","DOI":"10.1093\/jn\/132.8.2350S","article-title":"Epidemiological studies of folate and colorectal neoplasia: a review","volume":"132","author":"Giovannucci","year":"2002","journal-title":"J. Nutr"},{"key":"10.1093\/jn\/134.1.48_bib12","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1093\/ajcn\/70.4.495","article-title":"Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome","volume":"70","author":"James","year":"1999","journal-title":"Am. J. Clin. Nutr"},{"key":"10.1093\/jn\/134.1.48_bib13","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1086\/301825","article-title":"A second common mutation in the methylene tetrahydrofolate reductase gene: an additional risk factor for neural tube defects?","volume":"62","author":"Van der Put","year":"1998","journal-title":"Am. J. Hum. Genet"},{"key":"10.1093\/jn\/134.1.48_bib14","first-page":"1275","article-title":"Association of methylenetetrahydrofolate reductase polymorphism C677T and dietary folate with the risk of cervical dysplasia","volume":"10","author":"Goodman","year":"2001","journal-title":"Cancer Epidemiol. Biomark. Prev"},{"issue":"8","key":"10.1093\/jn\/134.1.48_bib15","doi-asserted-by":"crossref","first-page":"5606","DOI":"10.1073\/pnas.062066299","article-title":"A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate staus","volume":"99","author":"Friso","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"10.1093\/jn\/134.1.48_bib16","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1093\/carcin\/22.7.1019","article-title":"MTHFR C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into primary human lymphocyte DNA in vitro","volume":"22","author":"Crott","year":"2001","journal-title":"Carcinogenesis"},{"key":"10.1093\/jn\/134.1.48_bib17","first-page":"1089","article-title":"The effect of folic acid deficiency and MTHFR C677T polymorphism on chromosome damage in human lymphocytesin vitro","volume":"10","author":"Crott","year":"2001","journal-title":"Cancer Epidemiol. Biomark. Prev"},{"key":"10.1093\/jn\/134.1.48_bib18","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0027-5107(00)00065-8","article-title":"The in vitro micronucleus technique","volume":"455","author":"Fenech","year":"2000","journal-title":"Mutat. Res"},{"issue":"22","key":"10.1093\/jn\/134.1.48_bib19","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/S1359-6446(02)02502-3","article-title":"Chromosomal biomarkers of genomic instability relevant to cancer","volume":"7","author":"Fenech","year":"2002","journal-title":"Drug Discov. Today"},{"key":"10.1093\/jn\/134.1.48_bib20","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1093\/carcin\/18.7.1329","article-title":"Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of old men","volume":"18","author":"Fenech","year":"1997","journal-title":"Carcinogenesis"},{"key":"10.1093\/jn\/134.1.48_bib21","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1093\/carcin\/19.7.1163","article-title":"Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults","volume":"19","author":"Fenech","year":"1998","journal-title":"Carcinogenesis"},{"issue":"1\u20132","key":"10.1093\/jn\/134.1.48_bib22","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0027-5107(02)00086-6","article-title":"Micronuclei, nucleoplasmic bridges and nuclear buds induced in folic acid deficient human lymphocytes\u2014evidence for breakage-fusion-bridge cycles in the cytokinesis-block micronucleus assay","volume":"504","author":"Fenech","year":"2002","journal-title":"Mutat. Res"},{"key":"10.1093\/jn\/134.1.48_bib23","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1172\/JCI118763","article-title":"The effect of a subnormal vitamin B6 status on homocysteine metabolism","volume":"98","author":"Ubbink","year":"1996","journal-title":"J. Clin. Invest"},{"issue":"4","key":"10.1093\/jn\/134.1.48_bib24","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1093\/ajcn\/75.4.616","article-title":"High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic diseases and polymorphisms","volume":"75","author":"Ames","year":"2002","journal-title":"Am. J. Clin. Nutr"},{"key":"10.1093\/jn\/134.1.48_bib25","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1093\/hmg\/5.12.1867","article-title":"Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folic acid\/cobalamin disorders","volume":"5","author":"Leclerc","year":"1996","journal-title":"Hum. Mol. Genet"},{"key":"10.1093\/jn\/134.1.48_bib26","doi-asserted-by":"crossref","unstructured":"Moore, G. E. & Woods, L. K. (1976) Culture media for human cells\u2014RPMI 1603, RPMI 1634, RPMI 1640 and GEM 1717. In: Tissue Culture Association Manual, vol. 3, pp. 503\u2013508. Tissue Culture Association, Rockville, MD.","DOI":"10.1007\/BF00918753"},{"key":"10.1093\/jn\/134.1.48_bib27","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0531-5565(02)00061-X","article-title":"Demethylation of classical satellite 2 and 3 DNA with chromosomal instability in senescent human fibroblasts","volume":"37","author":"Suzuki","year":"2002","journal-title":"Exp. Gerontol"},{"key":"10.1093\/jn\/134.1.48_bib28","unstructured":"Norman, G. R. & Streiner, D. L. (1994) Biostatistics. Mosby-Year Book, St. Louis, MO."},{"issue":"1","key":"10.1093\/jn\/134.1.48_bib29","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0002-9440(10)63958-2","article-title":"Abnormal nuclear shape in solid tumours reflects mitotic instability","volume":"158","author":"Gisselson","year":"2001","journal-title":"Am. J. Pathol"},{"key":"10.1093\/jn\/134.1.48_bib30","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/sj.bjc.6600438","article-title":"Centrosomal abnormalities, multipolar mitoses and chromosomal instability in head and neck tumours with dysfunctional telomeres","volume":"87","author":"Gisselson","year":"2002","journal-title":"Br. J. Cancer"},{"issue":"7","key":"10.1093\/jn\/134.1.48_bib31","doi-asserted-by":"crossref","first-page":"3236","DOI":"10.1073\/pnas.97.7.3236","article-title":"Aneuploidy vs. gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy","volume":"97","author":"Li","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"issue":"1","key":"10.1093\/jn\/134.1.48_bib32","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1073\/pnas.97.1.303","article-title":"Chromosomal instability and cytoskeletal defects in oral cancer","volume":"97","author":"Saunders","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"10.1093\/jn\/134.1.48_bib33","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1126\/science.297.5581.565","article-title":"Connecting chromosomes, crisis and cancer","volume":"297","author":"Maser","year":"2002","journal-title":"Science"},{"key":"10.1093\/jn\/134.1.48_bib34","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1093\/carcin\/18.5.869","article-title":"Genetic and epigenetic aspects of DNA methylation on genome expression, evolution, mutation and carcinogenesis","volume":"18","author":"Zingg","year":"1997","journal-title":"Carcinogenesis"},{"key":"10.1093\/jn\/134.1.48_bib35","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nrg816","article-title":"The fundamental role of epigenetic events in cancer","volume":"3","author":"Jones","year":"2002","journal-title":"Nature Rev. Genet"},{"key":"10.1093\/jn\/134.1.48_bib36","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0027-5107(01)00168-3","article-title":"Recommended dietary allowances for genomic stability","volume":"480\u2013481","author":"Fenech","year":"2001","journal-title":"Mutat. Res"},{"issue":"1\u20133","key":"10.1093\/jn\/134.1.48_bib37","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/0009-8981(91)90235-5","article-title":"Betaine:homocysteine methyl transferase\u2014a new assay for the liver enzyme and its absence from human skin fibroblasts and peripheral blood lymphocytes","volume":"204","author":"Wang","year":"1991","journal-title":"Clin. Chim. Acta"},{"issue":"1","key":"10.1093\/jn\/134.1.48_bib38","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/mutage\/18.1.81","article-title":"A comparison of folic acid and 5-methyl tetrahydrofolate for prevention of DNA damage and cell death in human lymphocytes in vitro","volume":"18","author":"Wang","year":"2003","journal-title":"Mutagenesis"},{"key":"10.1093\/jn\/134.1.48_bib39","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1083\/jcb.140.6.1307","article-title":"Selective entrapment of extrachromosomally amplified DNA by nuclear budding and micronucleation during S phase","volume":"140","author":"Shimizu","year":"1998","journal-title":"J. Cell Biol"},{"key":"10.1093\/jn\/134.1.48_bib40","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1006\/excr.1994.1068","article-title":"Exclusion of specific human chromosomes into micronuclei by 5-azacytidine treatment in lymphocyte cultures","volume":"211","author":"Guttenbach","year":"1994","journal-title":"Exp. Cell Res"},{"key":"10.1093\/jn\/134.1.48_bib41","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/46052","article-title":"Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene","volume":"402","author":"Xu","year":"1999","journal-title":"Nature"},{"issue":"2","key":"10.1093\/jn\/134.1.48_bib42","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/ajmg.1320560218","article-title":"Chromosome instability in ICF syndrome: formation of micronuclei from multibranched chromosome 1 demonstrated by fluorescence in situ hybridisation","volume":"56","author":"Sawyer","year":"1995","journal-title":"Am. J. Med. Genet"},{"issue":"7","key":"10.1093\/jn\/134.1.48_bib43","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1093\/carcin\/16.7.1647","article-title":"Micronuclei induced by modulators of methylation: analogs of 5-azacytidine","volume":"16","author":"Stopper","year":"1995","journal-title":"Carcinogenesis"},{"issue":"9","key":"10.1093\/jn\/134.1.48_bib44","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/sj.ejhg.5201024","article-title":"Genetic polymorphisms in folate and homocysteine metabolism as risk factors for DNA damage","volume":"11","author":"Botto","year":"2003","journal-title":"Eur. J. Hum. Genet"},{"key":"10.1093\/jn\/134.1.48_bib45","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/jn\/132.2.283","article-title":"The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring Cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene","volume":"132","author":"Jacques","year":"2002","journal-title":"J. Nutr"},{"issue":"4","key":"10.1093\/jn\/134.1.48_bib46","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1124\/pr.54.4.599","article-title":"Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease","volume":"54","author":"DeBree","year":"2002","journal-title":"Pharmacol. Rev"},{"issue":"7","key":"10.1093\/jn\/134.1.48_bib47","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1182\/blood.V101.7.2483","article-title":"Genetic and nutritional factors contributing to hyperhomocysteinemia","volume":"101","author":"Kluijtmans","year":"2003","journal-title":"Blood"},{"issue":"3","key":"10.1093\/jn\/134.1.48_bib48","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0049-3848(01)00363-2","article-title":"Effects of homocysteine on proliferation, necrosis, and apoptosis of vascular smooth muscle cells in culture and influence of folic acid","volume":"104","author":"Buemi","year":"2001","journal-title":"Thromb. Res"},{"issue":"1\u20132","key":"10.1093\/jn\/134.1.48_bib49","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0009-8981(02)00092-X","article-title":"Serum total homocysteine increases with the rapid proliferation rate of tumor cells and decline upon cell death: a potential new tumor marker","volume":"321","author":"Sun","year":"2002","journal-title":"Clin. Chim. Acta"},{"issue":"4","key":"10.1093\/jn\/134.1.48_bib50","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/S0008-6363(01)00541-7","article-title":"Oxidant stress mechanism of homocysteine potentiating Con A-induced proliferation in murine splenic T lymphocytes","volume":"53","author":"Zhang","year":"2002","journal-title":"Cardiovasc. Res"},{"key":"10.1093\/jn\/134.1.48_bib51","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0009-8981(02)00174-2","article-title":"Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker","volume":"322","author":"Wu","year":"2002","journal-title":"Clin. Chim. Acta"},{"key":"10.1093\/jn\/134.1.48_bib52","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1016\/S0140-6736(01)06959-8","article-title":"Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control study","volume":"358","author":"Thompson","year":"2001","journal-title":"Lancet"},{"issue":"6","key":"10.1093\/jn\/134.1.48_bib53","first-page":"1619","article-title":"Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens","volume":"60","author":"Bonassi","year":"2002","journal-title":"Cancer Res"}],"container-title":["The Journal of Nutrition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022316623025853?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022316623025853?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/academic.oup.com\/jn\/article-pdf\/134\/1\/48\/24003067\/z4w00104000048.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T16:59:11Z","timestamp":1686589151000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0022316623025853"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,1]]},"references-count":53,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2004,1]]}},"alternative-id":["S0022316623025853"],"URL":"https:\/\/doi.org\/10.1093\/jn\/134.1.48","relation":{},"ISSN":["0022-3166"],"issn-type":[{"value":"0022-3166","type":"print"}],"subject":[],"published":{"date-parts":[[2004,1]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Methylenetetrahydrofolate Reductase C677T Polymorphism, Folic Acid and Riboflavin Are Important Determinants of Genome Stability in Cultured Human Lymphocytes","name":"articletitle","label":"Article Title"},{"value":"The Journal of Nutrition","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1093\/jn\/134.1.48","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Copyright \u00a9 2004 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}]}}