174 Introduction to Human Nutrition
this is the only way in which methyl-tetrahydrofolate
can be demethylated to yield free folate in tissues.
Methionine synthetase thus provides the link between
the physiological functions of folate and vitamin B 12.
Impairment of methionine synthetase activity in
vitamin B 12 defi ciency will result in the accumulation
of methyl-tetrahydrofolate, which can neither be uti-
lized for any other one-carbon transfer reactions nor
be demethylated to provide free folate.
This functional defi ciency of folate is exacerbated
by low tissue concentrations of methionine and an
accumulation of homocysteine, since the transulfura-
tion pathway to form cysteine from homocysteine is
regulated by the availability of cysteine: it is a biosyn-
thetic pathway rather than a pathway for disposal of
methionine and homocysteine.
Methylene-tetrahydrofolate reductase
and hyperhomocysteinemia
Elevated blood homocysteine is a signifi cant risk
factor for atherosclerosis, thrombosis, and hyperten-
sion, independent of factors such as dietary lipids and
plasma lipoproteins. About 10–15% of the popula-
tion, and almost 30% of people with ischemic heart
disease, have an abnormal variant of methylene-
tetrahydrofolate reductase, which is unstable, and
loses activity more quickly than normal. As a
result, people with the abnormal form of the enzyme
have an impaired ability to form methyl-tetrahydro-
folate (the main form in which folate is taken up by
tissues) and suffer from functional folate defi ciency.
Therefore, they are unable to remethylate homocys-
teine to methionine adequately and develop
hyperhomocysteinemia.
People with the abnormal variant of methylene-
tetrahydrofolate reductase do not develop hyperho-
mocysteinemia if they have a relatively high intake of
folate. This seems to be due to the methylation
of folate in the intestinal mucosa during absorption;
intestinal mucosal cells have a rapid turnover
(some 48 h between proliferation in the crypts and
shedding at the tip of the villus), and therefore it is
not important that methylene-tetrahydrofolate
reductase is less stable than normal, as there is still an
adequate activity of the enzyme in the intestinal
mucosa to maintain a normal circulating level of
methyl-tetrahydrofolate.
This has led to the suggestion that supplements of
folate will reduce the incidence of cardiovascular
disease. However, a number of intervention trials with
folate supplements have shown no reduction in death
from myocardial infarction, nor any decrease in all-
cause mortality, despite a signifi cant decrease in
plasma homocysteine. Similarly, in countries where
there has been mandatory enrichment of fl our with
folate for some years, there is no evidence of reduced
mortality from cardiovascular disease. It is possible
that elevated plasma homocysteine is not so much a
cause of atherosclerosis (although there are good
mechanisms to explain why it might be atherogenic)
as the result of impaired kidney function due to early
atherosclerosis. If this is so, the lowering of plasma
homocysteine by increasing folate intake would
not be expected to affect the development of
atherosclerosis.Folate in pregnancy
During the 1980s a considerable body of evidence
accumulated that spina bifi da and other neural tube
defects (which occur in about 0.75–1% of pregnan-
cies) were associated with low intakes of folate, and
that increased intake during pregnancy might be pro-
tective. It is now established that supplements of
folate begun periconceptually result in a signifi cant
reduction in the incidence of neural tube defects, and
it is recommended that intakes be increased by
400 μg/day before conception. (Closure of the neural
tube occurs by day 28 of pregnancy, which is before
the woman knows she is pregnant.) The studies were
conducted using folate monoglutamate and it is
unlikely that an equivalent increase in intake could be
achieved from unfortifi ed foods. In many countries
there is mandatory enrichment of fl our with folate,
and there has been a 25–50% decrease in the number
of infants born with neural tube defects since the
introduction of fortifi cation. The true benefi t is
greater than this, since some affected fetuses abort
spontaneously and there are few data on the number
of therapeutic terminations of pregnancy for neural
tube defects detected by antenatal screening; there-
fore, supplements are recommended. Where folate
enrichment is not mandatory, the advice is that all
women who are, or may be about to become, preg-
nant, should take supplements of 400 μg/day.Folate and cancer
Much of the regulation and silencing of gene expres-
sion that underlies tissue differentiation involves