DHFR
Dihydrofolate reductase (EC 1.5.1.3)
Publications[править]
The recent increase in the intake of folic acid by the general public through fortified foods and supplements, has raised safety concern based on early reports of adverse health outcome in elderly with low B12 status who took high doses of folic acid. These safety concerns are contrary to the 2015 WHO statement that "high folic acid intake has not reliably been shown to be associated with negative healeffects". In the folic acid post-fortification era, we have shown that in elderly participants in NHANES 1999-2002, high plasma folate level is associated with exacerbation of both clinical (anemia and cognitive impairment) and biochemical (high MMA and high Hcy plasma levels) signs of vitamin B12 deficiency. Adverse clinical outcomes in association with high folate intake were also seen among elderly with low plasma B12 levels from the Framingham Original Cohort and in a study from Australia which combined three elderly cohorts. Relation between high folate and adverse biochemical outcomes were also seen in the Sacramento Area Latino Study on Aging (High Hcy, high MMA and lower TC2) and at an outpatient clinic at Yale University where high folate is associated with higher MMA in the elderly but not in the young. Potential detrimental effects of high folic acid intake may not be limited to the elderly nor to those with B12 deficiency. A study from India linked maternal high RBC folate to increased insulin resistance in offspring. Our study suggested that excessive folic acid intake is associated with lower natural killer cells activity in elderly women. In a recent study we found that the risk for unilateral retinoblastoma in offspring is 4 fold higher in women that are homozygotes for the 19 bp deletion in the DHFR gene and took folic acid supplement during pregnancy. In the elderly this polymorphism is associated with lower memory and executive scores, both being significantly worse in those with high plasma folate. These and other data strongly imply that excessive intake of folic acid is not always safe in certain populations of different age and ethnical/genetic background.
MeSH Terms
- Aging
- Base Sequence
- Breast Neoplasms
- Female
- Folic Acid
- Humans
- Killer Cells, Natural
- Neoplasm Proteins
- Polymorphism, Genetic
- Sequence Deletion
- Tetrahydrofolate Dehydrogenase
Keywords
- Folate
- Folic acid
- Homocysteine
- Methylmalonic acid
- Vitamin B12
6R-L-Erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase (TH) activity and is a risk factor for cognitive decline and brain atrophy. Previous studies have shown that the decline in TH activity in the cerebral cortex of senescence-accelerated mouse prone 10 (SAMP10) mice is caused, at least in part, by a decrease in Fe, ferritin, and TH phosphorylation. We determined the concentrations of BH4 and the enzymes GTP cyclohydrolase-1,6-pyruvoyltetrahydropterin synthase and sepiapterin reductase (SPR) in the de novo pathway of BH4 biosynthesis. Dihydrofolate reductase (DHFR), which converts BH2 to BH4 in the salvage pathway of BH4 synthesis was also determined in the cerebral cortex of SAM mice at 3 and 12 months of age. The BH4 concentration was measured by HPLC, and the protein levels of enzymes involved in BH4 synthesis were measured by western blot analysis. At 12 months of age, BH4 concentration in the cerebral cortex of SAMP10 mice showed significantly higher values as compared to that of control mice. Further, the protein level of SPR in SAMP10 mice was significantly higher than that in SAMR1 mice at 3 and 12 months of age. In contrast to SPR, the protein level of DHFR in SAMP10 mice was significantly lower than that in SAMR1 mice. These results indicate that abnormal regulation of BH4 metabolism occurs in the cerebral cortex of SAMP10 where the dysfunction of the salvage pathway of BH4 synthesis may cause overproduction of BH4 through the de novo pathway, which is considered characteristic in the cerebral cortex of SAMP10 with aging. Therefore, there is a possibility that the excess amounts of BH4 lead to age-related brain dysfunction in the cerebral cortex of SAMP10.
MeSH Terms
- Aging
- Animals
- Biopterin
- Cerebral Cortex
- Chromatography, High Pressure Liquid
- Mice
- Phosphorylation
- Tetrahydrofolate Dehydrogenase