Supplements, vascular risk and homocysteine

Supplements to lower homocysteine concentration disappoint again
Epidemiological and genetic studies show a clear association between high serum concentrations of homocysteine and a higher risk of cardiovascular disease. So for more than a decade, researchers have been trying to reduce the risk of cardiovascular disease by giving people homocysteine lowering supplements of B vitamins and folic acid. Four large trials have already reported disappointing results. Now a fifth finds that B vitamins and folk acid don’t prevent cardiovascular disease, even in high risk patients with chronic, renal failure. Once again, the supplements brought down the participant’s homocysteine concentrations but not their risk of death , heart attack, stroke , or amputation .
No one can explain why the supplements don’t work in large trials, although one explanation is the attenuating effect of fortifying cereals with folic acid.
BMJ 22nd September 2007, supplements to lower homocysteine concentrations disappoint again vol 335, p587
Jamison et al JAMA 2007, Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease. Vol 298, 1163-1170.
Homocysteine is a non-protein-forming sulphur amino acid whose metabolism is at the intersection of two metabolic pathways: remethylation and transsulfuration . In remethylation, homocysteine acquires a methyl group from N-5-methyltetrahydrofolate or from betaine to form methionine. The reaction with N-5-methyltetrahydrofolate occurs in all tissues and is vitamin B]2 dependent, whereas the reaction with betaine is confined mainly to the liver and is vitamin B[2 independent. A considerable proportion of methionine is then activated by ATP to form S-adenosylmethionine (SAM). SAM serves primarily as a universal methyl donor to a variety of acceptors. 5-adenosyl homocysteine (SAH), the by-product of these methylation reactions, is subsequently hydrolysed, thus regenerating homocysteine, which then becomes available to start a new cycle of methyl-group transfer. This hydrolysis is a reversible reaction that favours the synthesis of SAH and that elevated cellular concentrations of this metabolite are likely to accompany all forms of hyperhomocysteinemia.
.In the transsulfuration pathway, homocysteine condenses will form cystathionine in an irreversible reaction catalyzed by the pyridoxal -5′- phosphate (PLP)-containing enzyme -cystathionine. β hydrolyzed by a second PLP-containing enzyme, γ-cystathionase, to cysteine and α-ketobutyrate. Excess cysteine is oxidized to taurine excreted in the urine.
Thus, in addition to the synthesis of cysteine, this transulfuration pathway effectively catabolises excess homocysteine which is not required for methyl transfer.
Selhub J 1999 Homocysteine vol 19, 217-8
Could it be that the emphasis is on the wrong system. What if the transsulfuration enzyme reaction system is lacking. There is synergy between the two pathways and this is nutritionally regulated. The addition of folic acid or other B vitamin may be of secondary rather than primary import.

Martin Eastwood
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