NUTRITION
October 1, 1999

Folate: New and Exciting Clinical Implications of an Old Vitamin

RMR
The B vitamin, folate, has certainly come a long way in the 50 years since it was first identified and synthesized in the 1940s. Initially, it was merely thought to serve a hemopoietic function, that is, was necessary for adequate production of blood cells and blood elements. Today, however, folate is used to prevent certain birth defects and its efficiency in preventing particular cancers and cardiovascular diseases is being explored.

Even in the decade after it was first identified, this hemopoietic function of folate was exploited for the development of the initial chemotherapeutic cancer agents. In 1949, Dr. Sidney Farber of Boston reported that a chemical compound that was nearly identical to folate (differing only by two atoms) was a potent antagonist of the vitamin and, thereby, could profoundly inhibit activity of the bone marrow.

This compound, which we now call methotrexate, proved to be the first effective cancer chemotherapeutic agent and was used to treat childhood leukemia. Today, methotrexate continues to be one of the most widely prescribed cancer chemotherapeutic agents.

JM
Early on, researchers exploited folate metabolism in the hopes of destroying disease-causing bacteria. The original antibiotics, the sulfonamides, are entirely based on their ability to inhibit folate synthesis in bacteria. Their efficacy was first identified in the 1930s before folate had been isolated: a Nobel Prize was awarded in 1939 for the discovery of sulfonamide antibiotics. It was not until the 1940s that scientists recognized that the means by which sulfonamide drugs kill undesirable bacteria is by inhibiting a chemical reaction in bacteria in which folate is synthesized.

In the last decade, newer insights and uses of folate metabolism have appeared.

Folate and Birth Defects

Folate can help prevent congenital neural tube defects, namely spina bifida and anencephaly. As early as the 1950s, scientists observed that women delivering babies with these neural tube defects had lower than usual dietary intakes of certain vitamins as well as depressed vitamin levels in their blood. Results from four prospective intervention trials emerged over the past several years, each of which demonstrated, in a very compelling fashion, that higher intakes of folate during the first six weeks of pregnancy could lower the incidence of this birth defect by approximately 80%.

Folate can help prevent congenital neural tube defects, namely spina bifida and anencephaly.

Two qualifications: first, the folate must be taken at the time of conception, which is frequently a period of time women are not yet aware that they are pregnant; second, we're not certain what dose of folate is necessary to convey protection against neural defects. Nevertheless, observational studies suggest that 400 ug/day is sufficient to see some benefit. Now, this level is important because the present RDA for women in the United States is only a 180 ug and the mean dietary intake of folate by women in the United States approximates the lower value as opposed to the desirable value.

As of January 1998, all uncooked cereal grain products in the United States were fortified at a concentration of 140 ug of folate per 100 g of grain as a result of this compelling body of studies. It is estimated that this will increase the daily intake of folate by women who habitually ingest low amounts of dietary folate by about 100 ug a day.

Folate and Cardiovascular Disease

RMR
It has been known for several decades that children born with a very rare inborn error of metabolism called congenital homocysteinuria develop very high levels of homocysteine in the blood and, typically, die in the second, third or fourth decade of life. An individual's folate status is a very important determinant of what blood homocysteine levels are. Homocysteine is disposed of by the cells of the body by a folate-dependent pathway. Therefore, diminished levels of folate will cause a build up of the precursor molecule, namely, homocysteine.

Vitamins B6 and B12 also play roles in the disposal of homocysteine from our bodies.

Joel, the last of the new clinical implications of folate metabolism is one in which you have a particular research interest: the issue of folate and its potential role as a cancer hemopreventive agent. Could you discuss this topic for us?

Folate and Cancer Prevention

JM
Under the microscope, a folate deficient cell (a so-called amegaloblastic cell) and a pre-cancerous cell (a so-called dysplastic cell) look very similar. This cytologic similarity between these two abnormal cells types was merely thought to be a coincidence until the 1980s when several investigators asked the question whether there might be some functional relationship between these two cell types.

Many human studies, as well as studies with animal models, indicate that higher levels of dietary folate convey some protection against the development of colorectal cancer. The latter observation is highly suggestive of a true cause and effect relationship between dietary folate and the risk of colorectal cancer.

Many human studies, as well as studies with animal models, indicate that higher levels of dietary folate convey some protection against the development of colorectal cancer.

Dietary folate has also been related to other epithelial cancers such as those of the uterine cervix, stomach, esophagus and lung. Nevertheless, the data are clearly most compelling for the colorectum.

The dose of folate necessary to convey some protection against cancer is not entirely clear but some study results suggest that as little as four times the basal requirement is enough to convey a significant amount of protection.

More Folate Is Not Always Better

I want to add that one has to be extremely cautious in giving large doses of folate to individuals who potentially have a colorectal neoplasm already existing. Cancer cells are rapidly proliferating and, as such, they have high requirements for folate. Giving large doses of folate to individuals who have existing cancers can actually accelerate the growth of those cancers.

Because it is a water-soluble vitamin, if you boil your vegetables in a large volume of water and then discard the water, much of the folate is discarded as well.

RMR
What are our dietary sources of folate?

JM
In the American diet, the fortified breakfast cereals, leafy green vegetables, orange juice and organ meats such as liver and kidney are all rich sources. Folate is a heat-liable vitamin, so overcooking can destroy its activity. Moreover, because it is a water-soluble vitamin, if you boil your vegetables in a large volume of water and then discard the water, much of the folate is discarded as well.

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