Moderate ‘multivitamin’ supplementation improved folate and vitamin B12 status in the elderly

Tal, Sari; Stern, Felicia; Polyak, Zeev; Ichelzon, Ina; Dror, Yosef

doi:10.1016/j.exger.2016.09.009

Cited by 1 publication

(1 citation statement)

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“…In these cases, it is thought that, at lower concentrations, these ligands engage higher-affinity antagonistic pockets within the LBD, but at higher concentrations, these ligands can also interact with lower-affinity agonistic sites. This complex dynamic with AhR, then, may ultimately help to explain the "Ushaped" relationship that has been widely observed between B12/ FA levels and various forms of morbidity (39), a phenomenon that has not been sufficiently explained by the 1C cycle alone.…”

Section: Discussionmentioning

confidence: 99%

Vitamin B12 and folic acid alleviate symptoms of nutritional deficiency by antagonizing aryl hydrocarbon receptor

Kim

Venkataraman

Jain

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.

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Section: Discussionmentioning

confidence: 99%