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Proteomic Study Shows Folate Deficiency In Rats Leads to Increase in Oxidative Stress

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A proteomic study by researchers at the French National Institute for Agricultural Research showed that rats that were deprived of folate for four weeks exhibited an increase in oxidative stress — a condition common to a lot of diseases, including cardiovascular disease, neurodegenerative diseases, and colon cancer.

The study, believed to be the first to use proteomics to analyze the effects of folate deficiency, supports previous biochemical studies showing that a lack of folate leads to oxidative stress.

The study is noteworthy to human health because epidemiological studies have linked folate deficiency to an increased risk of colon cancer, cardiovascular disease, and neurodegenerative diseases. Plus, the incidence of neural tube defects in American newborns has decreased since the US Food and Drug Administration recommended in 1992 that cereals and enriched grain products be fortified with folate.

"Folate is very interesting because it is associated with a number of chronic diseases," said Patrick Brachet, the last author of the study, which was published in this month's issue of the Journal of Nutrition. "But there is no demonstration of the causality of low folate status with the onset of these diseases. We're interested in determining the mechanism of the effect of folate deficiency at the metabolic level. What change occurs at the molecular and cellular level when we have folate deficiency?"

Folate is a water-soluble B vitamin that is naturally found in fruits, vegetables, and beans. In the United States, cereals are fortified with folate. In Europe, however, folate fortification is a controversial issue because some studies in mice suggest that high levels of folate could exacerbate tumors in people who have cancer, Brachet said.

Severe folate deficiency is not common in developed countries, said Brachet, who is a senior researcher in the Unit of Metabolic Diseases and Micronutrients at the INRA in Theix, France. However, specific subpopulations, including pregnant or lactating women and elderly people, may be at risk for moderate folate deficiency.

To analyze the molecular and cellular changes associated with folate deficiency, the researchers compared the proteomes of liver cells extracted from rats that had been fed normal diets, and rats that had been fed a diet containing no folate for four weeks. The researchers decided to focus on the liver because folate is concentrated and metabolized in that organ.

The researchers ran proteins from the rat liver cells on 2D electrophoresis gels. The proteins were extracted and analyzed using MALDI mass spectrometry. The scientists found nine spots that showed a significant difference in expression between folate-deficient rats and normal rats.

Proteins that were upregulated in the folate-deficient rats included glutathione peroxidase 1 and peroxiredoxin 6 — proteins believed to be involved in the response to oxidative stress — and MAWD binding protein, which has been associated with cancer.

Proteins that were downregulated in folate-deficient rats included cofilin 1, a protein linked to tumorigenesis, along with preproalbumin and a GRP 75 precursor, both of which are associated with response to oxidative stress and inflammation. A second spot, identified as MAWDBP, that had a lower isoelectric point than the upregulated MAWDBP, vanished almost completely with folate deficiency.

"Our conclusion is that what is very important with folate deficiency is the induction of oxidative stress, which is generally related to the onset of various diseases," said Brachet.

Brachet and his colleagues followed up their folate deficiency study with research into the effects of high levels of folate intake.

"What we observed with high levels of folate intake is that there is no increase in antioxidant enzymes," said Brachet. "That is something which will appear in our next paper."


The study is noteworthy to human health because epidemiological studies have linked folate deficiency to an increased risk of colon cancer, cardiovascular disease, and neurodegenerative diseases. Plus, the incidence of neural tube defects in American newborns has decreased since the FDA recommended in 1992 that cereals and enriched grain products be fortified with folate. … Folate fortification is a controversial issue in Europe because some studies in mice suggest that high levels of folate could exacerbate tumors in people who have cancer.

Brachet said that he and his research team would also like to follow up on their current folate studies by examining the molecular effects of folate deficiency on the vascular endothelium, colon tissue, and cerebral tissue.

"We want to focus next on these target tissues for diseases related to folate deficiency," said Brachet.

Brachet said he believes these tissues will also exhibit changes in their level of expression of proteins involved in oxidative stress response.

"I think the proteins involved in antioxidant response are a universal response of tissues to oxidative stress," he said.

Brachet said that it is too early to tell if the proteins that have been discovered could have any therapeutic effect on diseases related to folate deficiency.

"With these proteins, we would like to investigate further how they are regulated by a decrease in concentration folate at the transcription level, translation level, and post-translationally," he said.

Brachet added that his proteomic study is not likely to have any effect on the debate in Europe over whether or not to fortify foods with folate.

"The problem is that in cancer treatments, very often they use drugs that are anti-folate because high levels of folic acid were shown in mice with colorectal cancer to result in higher levels of tumor incidence," Brachet said. "If at the same time, people are consuming foods with high folate, it would not be good."

— Tien-Shun Lee ([email protected])

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