The mantra “the more, the better” doesn’t always apply for folic acid, a new study finds. A key liver enzyme converts folic acid to a useful form much more slowly in humans than it does in rats, researchers report online August 24 in the Proceedings of the National Academy of Sciences. The slow rate suggests that higher doses of folic acid may not be any better for the body than the daily recommended dose.

Chemists created folic acid in 1945 as a nutritional supplement because people weren’t getting enough folate, the natural form of the supplement, in their diets. Among pregnant women, this deficiency is strongly associated with birth defects such as spina bifida.

Folates help the body use the fuel it ingests, explains study coauthor Steven Bailey of the University of South Alabama in Mobile. To do the job of its natural counterpart, folic acid must first be activated by a liver enzyme called dihydrofolate reductase, or DHFR. But the new study shows that the amounts of this enzyme in the liver are limited, meaning excess folic acid may go to waste, unable to perform its task.

“As the dose of folic acid is increased, one reaches a point at which DHFR cannot go any faster, and unconverted folic acid begins to accumulate in the blood,” Bailey says. “Most of this is cleared by the kidneys into the urine, but only after many hours.”

Bailey and University of South Alabama colleague June Ayling measured activated folic acid in fresh human livers, most of them removed from organ donors for whom no recipient was available, and compared the amounts with amounts of activated folic acid in fresh rat livers.

The researchers found that the average rate of folic acid activation in rat livers was 56 times higher than it was in human livers. Human livers also showed much greater variability in their activation rate than the rat livers did, implying that some people may be able to use more folic acid at any given time than others.

Researchers think high doses of activated folic acid could reduce blood levels of the amino acid homocysteine, which studies have linked with cardiovascular diseases. But recent clinical trials testing the effects of folic acid doses as high as 5 milligrams per day (the recommended dose is 0.4 milligrams) on risks of heart disease, stroke and Alzheimer’s disease have shown mixed results. Bailey says this new work may explain why.

The study “shows that you just can’t keep increasing the dose of folic acid and getting a better outcome,” says nutritional biochemist Eoin Quinlivan of the University of Florida in Gainesville. In fact, increasing the levels of folic acid “may be counterproductive,” he says. The study also found evidence that unactivated folic acid in the blood may slightly decrease DHFR’s activity.

Recent studies have reported that high levels of unactivated folic acid may exacerbate preexisting prostate or colon cancers. But both Quinlivan and Bailey say it is too soon to say what effect the higher doses of unmetabolized folic acid may have on a person and that more research on the long-term effects of high doses of the supplement is needed.

“There’s every reason to continue taking folic acid” to prevent serious birth defects, Bailey says. He adds that his study shows that adult human livers can process the daily recommended dose.

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