Metabolic Functions

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The role of folate in anemia is well established. Anemia was the first deficiency symptom associated with the vitamin.1-3 Folate deficiency is characterized by the inability of erythrocytes to replicate normally,16 resulting in a megaloblastic anemia.17 This is important to athletes, particularly endurance athletes, because of the need to transport oxygen. The large oval cells of this anemia have less hemoglobin and a reduced capacity to carry oxygen through the blood.

Because folate is necessary for DNA synthesis, it is important in the reproduction of cells, particularly those that rapidly proliferate as erythrocytes, gastrointestinal epithelium and fetal cells. The relationship between folate deficiency and neural-tube defects is also well established. Folate supplementation around conception greatly decreases the risk of having an offspring with a neural-tube defect.18-21

The relationship between folic acid and homocysteine has been the focus of considerable research. Homocysteine is an intermediate sulfur-containing amino acid that is formed during normal metabolism and converted to the essential amino acid methionine. THFA, along with vitamins B6 and B12, is important in the conversion of homocysteine to methionine. Homocysteine is produced as a result of methylation reactions. The two most productive methyltransferases are guanidinoacetate methyltransferase and phosphatidylethanolamine N-methyltransferase. The first produces creatine and the latter produces phosphatidylcholine.22 Both reactions increase plasma homocysteine. The methylation of guanidinoacetate to produce creatine requires more methyl groups than all other methylation reactions combined.23 This is significant to athletes because creatine production is a vital factor in exercise. Because of the diseases associated with hyperhomocysteinemia, its production during exercise should be of concern to the athlete.

Hyperhomocysteinemia has been suspected as a risk factor for atherosclerosis,24 particularly with diabetics.25 Elevated homocysteine has now emerged as a major player in atherosclerosis26-28 and Alzheimer's.29-32 It may have a causative role in some cancers,33-36 and possibly increases susceptibility to osteoporotic fractures.3738 It may cause chromosome damage,42 and is elevated in stroke patients,39 patients with depression,40 dementia,29 and those having Parkinson's disease who are taking L-DOPA.2241 Simultaneous with homocysteine research, folic acid is emerging as the vanguard nutrient to possibly prevent all of the diseases mentioned, because it has been shown to lower plasma homocysteine.4344 Hyperhomocysteinemia has been correlated with decreased levels of either B12 or folate.2545 Several studies have reported that folate treatments significantly reduced elevated homocysteine in chronic renal insufficiency and hemodialysis patients,46 while others reported a beneficial effect from high daily doses of folate and B6,47 or with high daily dosing of folate, B6 and B12.48 Research completed in the Netherlands found the combined supplementation of folate, B6 and B12 to reduce homocysteine by 30% compared with a placebo.49

Most of the research with homocysteine has to do with methylation. Feron and Vogelstein point out that the loss of DNA methylation has been shown to inhibit chromosome condensation and thus might lead to mitotic nondisjunction.50 The U.S. Nurses' Health Study suggested that an increase in dietary folate and vitamin B6 above the normal requirements may be a primary preventive measure against coronary heart disease51 and the Kuopio Ischemic Heart Disease Risk Factor Study found a significant inverse relationship between folate intakes and acute coronary events in men.52 Clark and co-workers believe hyperhomocysteinemia to be a weak risk factor for asymptomatic extracranial carotid atherosclerosis.53 Majors and co-workers suggested that homocysteine accumulation might promote an increase in both collagen production and total protein synthesis, which could increase the risk for vascular disease. Majors quotes others that indicate elevated homocysteine may promote the oxidation of LDL and have the potential to increase free radicals.54 Moustapha et al. believe their research confirms that patients with elevated plasma homocysteine levels have a greater likelihood of developing thrombotic or atherosclerotic complications.55 Stanger et al., investigating the management of homocysteine, folate and B vitamins in treatment of cardiovascular and thrombotic diseases, reported that a plasma homocysteine concentration of 10 pmol/l could produce a linear dose-response relationship for increased risk of cardiovascular disease. The researchers further stated that hyperhomocysteinemia, as an independent risk factor for cardiovascular disease, is thought to be responsible for 10% of the total risk.56

In a review of hyperhomocysteinemia, Virdis and co-workers conclude that experimental evidence exists to suggest hyperhomocysteinemia can be considered an independent risk factor for the recurrence of cardiovascular events and could be a predictor of new cardiovascular events.26 Others also consider hyperhomocysteinemia to be an independent risk factor for coronary disease.27,28 Despite all of the information relating homocysteine with cardiovascular disease, the American Heart Association has yet to declare hyperhomocysteinemia as a major risk factor for cardiovascular disease.57

Aside from folate's relationship with homocysteine, the latest-breaking news about folate is promising. Wilmink et al. completed a case-controlled study on the effect of folate and vitamin B6 intake on peripheral arterial occlusive disease in men over the age of 50. Their model suggests that a daily increase of folate by one standard deviation decreased the risk of peripheral arterial occlusive disease by 46%. This was independent of serum levels of homocysteine.58 Moat and others observed that folic acid supplementation could reverse endothelial dysfunction observed in patients with cardiovascular disease, also independent of homocysteine levels.59 When adolescents and children with type 1 diabetes were given 5 mg of folic acid for 8 weeks, there was an improvement in endothelial function independent of homocysteine.60

The relationship between elevated homocysteine and athletes is important, because research suggests that endurance exercises may cause a significant increase in plasma homocysteine. Twenty-five percent of the recreational endurance athletes studied in one trial exhibited hyperhomocys-teinemia in association with low intakes of folate and B12.61 Another study completed with rats indicated that exercise increased endothelial nitric oxide. If this is true in humans, it may have a protective effect against elevated homocysteine, which decreases nitric oxide.62 A Dutch study did not find a significant effect on plasma homocysteine concentration due to exercise63 while another study suggests that proper diet and exercise may lower homocysteine levels.64

Research at Tufts University indicated that the elderly are susceptible to metabolic and physiological changes that affect B12, B6 and folate status. Low gastric pH enhances the absorption of B12 and folate, and many of the elderly have decreased production of gastric acid.65

The serum homocysteine status is affected by many variables and, in most cases, elevated homocysteine is probably the result of a combination of factors, including gender, age, smoking, nutrition, coffee and alcohol.66

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