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Methylering er en grundlæggende proces inden for cellefysiologi. Det indebærer binding af en methylradikal gruppe (CH3) til andre molekyler, og den er essentiel bl.a. for DNA’s regulering af genekspression, for aktivering i kroppen af nogle vitaminer og afgiftningsprocessen i leveren.
Hold godt fast i sædet, når Montse her forklarer noget om en af tidens trends: Er det vigtigt at vide noget om methylering, når vi spiser, og især når vi spiser kosttilskud?
Af Montse Farré Hernández
For at gøre det meget simpelt kan vi sige, at disse methyler er en slags “plaster”, der tilføjes her og der, så tingene fungerer ordentligt i den fantastiske transformationsfabrik, som kroppen er.
Hele methyleringscyklussen er meget kompleks, og vi dykker ikke helt ned i de svære kemiske forklaringer i denne artikel. Men jeg vil nævne nogle eksempler, så du får en bedre forståelse af, hvordan den fungerer, og hvorfor den er så vigtig.
DNA-methylering er en epigenetisk mekanisme, der involverer overførsel af en methylgruppe, som regulerer genekspression ved at rekruttere proteiner involveret i genundertrykkelse eller ved at hæmme bindingen af transskriptionsfaktorer til DNA. DNA-methylering er af afgørende betydning for at opretholde ”gendæmpning”, og hvis den ikke fungerer, som den skal, er der højere risiko for udvikling af nogle sygdomme (1, 2).
Det handler om at aktivere næringsstoffer, så de kan anvendes af cellerne
Et andet eksempel, hvor methylering er meget vigtig, er folinsyre, som er den syntetiske form af B9-vitamin, og som også findes i form af folater i fødevarer, især i de grønne bladgrøntsager, nogle frugter, bælgfrugter og indmad. Folinsyre og folater har også brug for methylering, så de aktiveres i kroppen og kan bruges i vores celler og udføre deres funktioner. Enzymet MTHFR (methylentetrahydrofolat reduktase) er ansvarlig for denne aktiveringsproces, da enzymet omdanner folat til methylfolat (3, 4), som bliver til den aktive form, der kan bruges i vores celler og fx i hjernen, da methylfolat kan passere blod-hjerne-barrieren, mens folat ikke kan. Men på samme tid har MTHFR-enzymet brug for en stor nok mængde af folat gennem kosten, for at det kan fungere optimalt, dvs. at de arbejder i en indbyrdes cyklus. Den kaldes for en folatcyklus.
Som vi ved, er folinsyre ekstremt vigtig, især under graviditet, og mangel er en højrisikofaktor for neuralrørsdefekter (NTDs), en tilstand, der kan opstå hos fosteret (5).
Homocystein i de rette mængder. Ikke mere, ikke mindre
På samme tid er den biokemiske folatcyklus meget afhængig af og tæt knyttet til vitamin B12 og B6, der samarbejder som en gruppe i mange funktioner i kroppen. Hvis processen ikke foregår korrekt hos en enkelt medspiller, vil det påvirke samarbejdet for hele gruppen, som det sker fx i homocystein-methionin-cyklussen.
Methionin er en svovlaminosyre, som i sit stofskifte producerer en mellemforbindelse kaldet homocystein. Forbindelsen er meget giftig, da dens ophobning i blodet øger risikoen for hjerte-kar-sygdomme, inflammationer og neurodegenerative sygdomme (6, 7, 8). Derfor genbruger kroppen homocystein, og omdanner den igen til methionin gennem det tætte samarbejde mellem disse tre vitaminer, så homocystein ikke akkumuleres i blodet. Det kræver en god leverfunktion, som du kan læse om sidst i artiklen.
Vegetarer og veganere kan ikke klare sig uden B12 fra kosttilskud
Måling af homocystein i blodet er en af de markører, der bruges til bl.a. at tjekke, om methyleringsprocessen fungerer korrekt (9). Den bruges dog også til at tjekke, om der er tilgængeligt aktivt B12- og B9-vitamin i blodet til at udføre deres arbejde, og det punkt er særligt vigtig for vegetarer og veganere, da B12 kun findes i animalske fødevarer. Er du vegetar eller veganer, er det utroligt vigtigt, at du tager tilskud af B12 vitamin, så du sikrer dig, at du ikke kommer til at mangle det livsnødvendige vitamin (10, 11, 12, 13).
B12-vitamin cobalamin findes i forskellige kemiske former
Hydroxocobalamin er den mest almindelige form i fødevarer og cyanocobalamin (en af de mest anvendte former i kosttilskud og berigede fødevarer, fordi den er meget stabil) og er ikke-fysiologiske former for cobalamin, som betyder, at de skal omdannes for at udføre deres arbejde i vores celler. I kroppen forvandles de hurtigt til methylcobalamin (den form for B12, som findes i blodet og også i nogle få fødevarer) og 5’deoxyadenosylcobalamin (den måde, B12 opbevares i leveren), som er de fysiologiske aktive former eller co-enzymer af vitamin B12.
Cyanocobalamin er den syntetiske form af B12, der bruges til mange kosttilskud og i berigede fødevarer, og den er lavet med en “cyanid-donor”. Den bruges meget, fordi den er billigere end andre former og er den mest stabile form, fordi cyanidmolekylet har den største tiltrækning til cobalamin og dermed beskytter det, så det ikke bliver ødelagt af forskellige forhold, som fx meget høje temperaturer, eksponering for lys eller lang tids opbevaring. Når cyanocobalamin absorberes, konverteres det hurtigt til hydroxocobalamin, hvor cyanidet “kasseres” i processen. Derefter omdannes hydroxo B12 til methyl B12 og adenosyl B12, som er de aktive former i kroppen.
Allerede forvirret? Det er også et meget indviklet emne, men det er vigtigt at forstå, at der ikke er nogen grund til at synes mere eller mindre om den ene eller den anden form for cobalamin, og blot fordi ordet ”cyanid” indgår, bliver det ikke til en giftig proces eller til et farligt kosttilskud …
Når vi taler om methylcobalamin, er der ingen tvivl om, at det er den aktive form, som kroppen kan bruge med det samme. Problemet er, at den er dyrere at producere og mindre stabil, og som kosttilskud er den ikke mere effektiv end cyanocobalamin og hydroxocobalamin.
Noget af cyanocobalaminen og hydroxocobalaminen reduceres i cellernes mitokondrier og mikrosomer til 5’deoxyadenosylcobalamin, og resten omdannes til methylcobalamin.
Enhver ændring i de forskellige metaboliske trin kan føre til arvelige defekter i B12-vitamin-metabolismen, der er karakteriseret ved homocystinuri og methylmalonsyreuri eller begge dele. Det er begge sjældne tilstande, som udelukkende opstår ved medfødte enzymdefekter – se senere.
B6, B9 og B12 er makkere i processen
Som bekrevet er B12 også en vigtig del af methyleringen sammen med B9 og B6, hvor alle tre vitaminer hjælper til i omdannelsen af homocystein til methionin. Den aktive form af vitamin B12 i denne reaktion er methylcobalamin, og dens mangel vil skabe en akkumulering af folat i en form, som ikke kan bruges i cyklussen og dermed føre til en ophobning af homocystein i blodet med en øget risiko for forskellige sygdomme nævnt her i artiklen (14) som konsekvens.
Et andet eksempel på methylering er, at den er nødvendig i fase II-afgiftning af leveren, hvor de meget toksiske mellemliggende metabolitter, fra vores egen metabolisme eller fra lægemidler, der genereres i fase I, forberedes til eliminering via for eksempel urin eller sved (15). I fase II bruges forskellige enzymer og veje til neutralisering af disse meget toksiske metabolitter, og én af disse veje er methylering. En nedsat evne eller en fejl i denne funktion vil give en forhøjet ophobning af de toksiske metabolitter i kroppen.
Vi kan derfor konkludere, at genetiske defekter af nogle enzymer, der er involveret i methyleringsprocessen, eller ernæringsmæssige mangler af især folinsyre/folat, vitamin B6 og B12 fører til en øget risiko for forskellige sygdomme (16).
Generelt kan langt de fleste af os methylere uden problemer, men der findes nogle genetiske polymorfismer af MTHFR-genet, som kan have betydning for hele processen.
En polymorfisme er en genetisk variant i DNA-sekvensen mellem individer af samme art, fundet med en frekvens større end en procent (under en procent kaldes det en mutation). Varianter af MTHFR-genet kan forårsage lave niveauer af MTHFR-enzymet. Som vi har set, er dette enzym nødvendigt for at omdanne folater fra kosten eller den syntetiske folsyre/folinsyre fra kosttilskud til methylfolat, som er den aktive form i kroppen. Når der produceres lavere niveauer af dette enzym, end hvad der er nødvendigt, kan folsyre/folat ikke omdannes til methylfolat, og dermed sker der en ophobning af homocystein i blodet og en øget risiko for sygdomme hos spædbørn og i sjældne tilfælde senere i livet.
Kan man diagnosticere disse genetiske polymorfismer af MTHFR-genen ?
Ja, genfejl i MTHFR-genet kan diagnosticeres med blodprøver, hvor der ses homocystinuri, forhøjet homocystein og nedsat metionin i plasma. Dette bekræftes ved nedsat aktivitet af MTHFR i leukocytter, som lægen eventuelt kan måle.
Disse polymorfismer er medfødte arvelige sygdomme, og derfor debuterer man oftest med udviklingshæmning i det første leveår eller i den tidlige barndom, men i nogle tilfælde kan problemerne også først vise sig senere. Forekomst er heldigvis meget sjælden.
Hvilke symptomer?
Hos nyfødte og småbørn ses der ofte spiseproblemer, påvirket bevidsthed, ophobning af væske i hjernen, nedsat muskelkraft og vejtrækningspauser under søvn.
Hos ældre børn ses ofte epilepsi, forsinket udvikling og udviklingsdefekt i hjernen.
Senere i livet er hyppige debutsymptomer fx følelsesløshed eller smerte i fødderne, påvirket gangfunktion, spasticitet eller psykiatriske problemer som fx skizofreni.
Er der behandling?
Ja. Denne sygdom skal behandles og kontrolleres hos lægen, som vil behandle den med betain, folinsyre, metionin, B12- og B6-vitamin (17).
Spis sundere!
Vi kan også have mangel af disse vigtige B6-, B9- og B12-vitaminer på grund af ubalanceret kost, nedsat optagelse af næringsstoffer og/eller overbelastet lever, hvilket kan føre til en nedsat methyleringsproces. Her er løsningen at spise godt med folater gennem kosten; de findes især i grønne bladgrøntsager, nogle frugter, bælgfrugter og indmad. B12-vitamin findes i de animalske fødevarer som fx fjerkræ, kød, fisk, æg, og hvis du spiser vegetarisk eller vegansk, skal B12 indtages via kosttilskud, da der, set fra et videnskabeligt synspunkt, ikke findes en brugbar aktiv form af B12 i den vegetabilske verden. Dertil skal du også huske B6-vitamin, som især findes i laks, tun, kikærter, kylling, pistacienødder, kartofler.
Og til sidst skal vi ikke glemme leveren, da leveren er det vigtigste organ til syntese af methylgrupper, og en overbelastet lever eller en lever med nedsat funktion har også konsekvenser for hele processen. Du kan passe godt på din lever ved at spise en sund og varieret kost baseret på friske grøntsager og frugt, især kålfamilien, artiskokker, rucola, porre, løg, hvidløg, asparges og bær, samt undgå raffineret sukker og forarbejdede produkter, undgå alkohol, have en god håndtering af stress, en god søvn, og hvis du vil give leveren en hånd, er den glad for især bitre urter, fx marietidsel eller mælkebøtte, som du kan drikke i te eller tilsætte til din salat i form af mælkebøtteblade.
Referencer:
- Moore, L., Le, T. & Fan, G. DNA Methylation and Its Basic Function. Neuropsychopharmacol38, 23–38 (2013). https://doi.org/10.1038/npp.2012.112
- Kulis M., Esteller M. DNA methylation and cancer. Adv Genet. 2010;70:27-56. https://doi 10.1016/B978-0-12-380866-0.60002-2 PubMed PMID: 20920744
- Levenseller Levin B., Varga E. MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Base Literature. J Genet Couns. 2016 Oct;25(5):901-11. https://doi:10.1007/s10897s10897-016-9956-7 PubMed PMID: 27130656
- Liew SC, Das Gupta E. C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet. 2015 Jan;58(1):1-10. https:/doi: 10.1016/j.ejmg.2014.10.004 Epub 2014 Nov 4. PubMed PMID: 25449138
- Wang L, Shangguan S, Xin Y, et al. Folate deficiency disturbs hsa-let-7 level through methylation regulation in neural tube defects. J Cell Mol Med. 2017 Dec;21(12):3244-3253. doi: 10.1111/jcmm.13228. Epub 2017 Jun 19. PMID: 28631291
- Ganguly P, Alam SF. Role of homocystein in the development of cardiovascular disease. Nutr J. 2015 Jan 10;14:6. doi: 10.1186/1475-2891-14-6. PMID: 25577237
- Elsherbiny N, Sharma I, et al. Homocysteine Induces Inflammation in Retina and Brain. Biomolecules. 2020 Mar 3;10(3):393. doi: 10.3390/biom10030393 PMID: 32138265
- Smith AD, Refsum H. Homocysteine, B Vitamins, and Cognitive Impairment. Annu Rev Nutr. 2016 Jul 17;36:211-39. doi: 10.1146/annurev-nutr-071715-050947. PMID: 27431367
- Shen W, Gao C, et al. Homocysteine-methionine cycle is a metabolic sensor system controlling methylation-regulated pathological signaling. Redox Biol. 2020 Jan;28:101322. doi: 10.1016/j.redox.2019.101322. Epub 2019 Sep 12. PMID: 31605963
- Norris J., Vitamin B12 https://veganhealth.org/vitamin-b12/
- Messina V., Vitamin B12: A Vegan Nutrition Primer https://www.theveganrd.com/vegan-nutrition-101/vegan-nutrition-primers/vitamin-b12-a-vegan-nutrition-primer/
- Aguirre JA, Donato ML, et al. Serious neurological compromise due to vitamin B12 deficiency in infants of vegan and vegetarian mothers. Arch Argent Pediatr. 2019 Aug 1;117(4):e420-e424. doi: 10.5546/aap.2019.e420. PMID: 31339288
- Zeuschner CL, Hokin BD, et al. Vitamin B12 and vegetarian diets. Med J Aust. 2013 Augt 19;199(S4):S27-32. doi: 10.5694/mja11.11509. PMID: 25369926
- Alemán G, Tovar A, Torres N. Homocysteine metabolism and risk of cardiovascular diseases: importance of the nutritional status on folic acid, vitamins B6 and B12. Rev Invest Clin. Mar-Apr 2001;53(2):141-51. PMID: 11421110
- Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010 Jun;154(2):103-16. doi: 10.5507/bp.2010.017. PMID: 20668491
- Alemán G, Tovar A, Torres N. Homocysteine metabolism and risk of cardiovascular diseases: importance of the nutritional status on folic acid, vitamins B6 and B12. Rev Invest Clin. Mar-Apr 2001;53(2):141-51. PMID: 11421110
- Huemer M, Diodato D, et al. Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J Inherit Metab Dis. 2017 Jan;40(1):21-48. doi: 10.1007/s10545-016-9991-4. Epub 2016 Nov 30. PMID: 27905001
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