B-vitamins, homocysteine metabolism and CVD

Abstract

The present review focuses on the B-vitamins, i.e. folate, vitamin B 12 , vitamin B 6 and riboflavin, that are involved in homocysteine metabolism. Homocysteine is a S-containing amino acid and its plasma concentrations can be raised by various constitutive, genetic and lifestyle factors, by inadequate nutrient status and as a result of systemic disease and various drugs. Hyperhomocysteinaemia is a modest independent predictor of CVD and stroke, but causality and the precise pathophysiological mechanism(s) of homocysteine action remain unproven. The predominant nutritional cause of raised plasma homocysteine in most healthy populations is folate insufficiency. Vitamin B 12 and, to a lesser extent, vitamin B 6 are also effective at lowering plasma homocysteine, especially after homocysteine lowering by folic acid in those individuals presenting with raised plasma homocysteine. However, riboflavin supplementation appears to be effective at lowering plasma homocysteine only in those individuals homozygous for the T allele of the C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. This gene codes for the MTHFR enzyme that produces methyltetrahydrofolate, which, in turn, is a substrate for the remethylation of homocysteine by the vitamin B 12 -dependent enzyme methionine synthase. Individuals with the MTHFR 677TT genotype are genetically predisposed to elevated plasma homocysteine, and in most populations have a markedly higher risk of CVD.Homocysteine: Folate: Vitamin B 12 : Vitamin B 6 : Riboflavin Epidemiological and experimental evidence is accumulating to indicate a probable role for certain B-vitamins in the prevention of CVD. Active forms of four B-vitamins, i.e. folate, vitamin B 12 , vitamin B 6 and riboflavin, are involved in the metabolism of a S-containing amino acid, homocysteine. Homocysteine metabolism links the methionine cycle with the folate cycle (Fig. 1). In most tissues and cells the major, or only, pathway for the conversion of homocysteine to methionine is the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine, catalysed by the vitamin B 12 -dependent enzyme methionine synthase. One product of this reaction, methionine, can donate the methyl group via the activated form of methionine S-adenosylmethionine to a range of substrates, including proteins, phospholipids and DNA. The other product of the methionine synthase reaction, tetrahydrofolate, is reconverted to 5-methyltetrahydrofolate via the folate cycle. The reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate in the folate cycle is catalysed by the methylenetetrahydrofolate reductase (MTHFR) enzyme, which has a FAD (derived from riboflavin) prosthetic group. The metabolically-active form of vitamin B 6 , pyridoxal phosphate, is an enzyme cofactor for cystathionine b-synthase, which is involved in the catabolism of homocysteine to sulfate in the transsulfuration pathway (Fig.

Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence

“…As noted earlier, B 6 facilitates the breakdown of homocysteine to cysteine and glutathione. 9 Recent data 22 indicate that vitamin B 6 is an important factor. Assuming that the one-carbon pathway is important in the etiology of colorectal neoplasia, even with additional dietary folate, it does not appear that this will optimally reduce risk through this pathway; therefore, further attention should be given to factors such as B 6 .…”

“…9 Homocysteine levels can be increased by the presence of genetic factors, physiological defects and by use of certain drugs 10 as well as by deficiencies in folate, vitamins B 12 and B 6 , necessary cofactors for its conversion to methionine. 9 Few data exist on the relation between homocysteine and colorectal neoplasia. 3,4 …”

“…8 Homocysteine, a biochemical marker of folate status, is an amino acid that is metabolized via remethylation into methionine, facilitated by folic acid and vitamin B 12 or trans-sulfuration to cysteine, facilitated by vitamin B 6 . 9 Homocysteine levels can be increased by the presence of genetic factors, physiological defects and by use of certain drugs 10 as well as by deficiencies in folate, vitamins B 12 and B 6 , necessary cofactors for its conversion to methionine. 9 Few data exist on the relation between homocysteine and colorectal neoplasia.…”

“…9 Homocysteine levels can be increased by the presence of genetic factors, physiological defects and by use of certain drugs 10 as well as by deficiencies in folate, vitamins B 12 and B 6 , necessary cofactors for its conversion to methionine. 9 Few data exist on the relation between homocysteine and colorectal neoplasia. 3,4 In 1996, the United States Food and Drug Administration (FDA) issued a regulation for the prevention of neural tube defects (NTDs), requiring that all enriched cereal grain products (i.e., flour, rice, pasta, breads, etc.)…”

The significance of folate supplementation

“…Thus, according to USA law, dietary supplements can be orally taken either in isolation or as a supplement to one's daily diet, but they cannot be a substitute for eating complete meals. A dietary supplement can be given without any prescription, according to European law, and constitutes a substance that is safe to the body; both in quantity and quality [1]. Supplements should be tailored to the requirements of a patient's individual nutritional status.…”