Tuesday, July 3, 2007

Folate homeostasis

The majority of 5-methyl-THF arriving at the liver
from the intestine and taken up is not demethylated
and converted to polyglutamate; instead it is quickly
released for distribution to extrahepatic tissues. The
initial route for this distribution is the enterohepatic
circulation, whereby the folate is discharged into the
bile and subsequently reabsorbed by the small intestine
before re-entering the systemic circulation.
Accompanying 5-methyl-THF in the bile are larger
amounts of non-methylated tetrahydrofolates which
represent folates salvaged from dying cells such as
senescent erythrocytes and hepatocytes (Shin et al.,
1995). Any folic acid that might have been absorbed
and released into the portal circulation without
modifi cation is exclusively taken up by the liver and
either converted into one-carbon derivatives of THF
prior to rapid release into bile or polyglutamated and
incorporated into the hepatic folate pool (Steinberg,
1984). Hepatic reduction and derivatization of folic
acid provides another source of non-methylated tetrahydrofolates
present in bile (Shin et al., 1995).
The recycling of folate via the enterohepatic pathway
may account for as much as 50% of the folate
that ultimately reaches the extrahepatic tissues. Disruption
of the enterohepatic cycle by bile drainage
results in a fall of the serum folate level to 30–40% of
normal within 6 hours – a much more dramatic drop
than that seen with a folate-defi cient diet. Eventually,
the serum folate level stabilizes, despite continuing
losses in the bile. This suggests a net fl ux of folate into
the plasma compartment from tissue pools. Release
of stored folate from cells of any tissue requires hydrolysis
of the polyglutamates to monoglutamates by
intracellular conjugase.
The maintenance of a normal level of plasma folate
depends on regular increments of exogenous folate
from the diet. The enterohepatic circulation of folate
evens out the intermittent intake of dietary folate. The
liver plays a major role in maintaining folate homeostasis
because of its capacity to store about 50% of the
total body folate, its relatively rapid folate turnover,
and the large folate fl ux through the enterohepatic
circulation (Steinberg, 1984). In situations of dietary
folate defi ciency, the liver does not respond by releasing
its folate stores. Rather, the non-proliferating,
less metabolically active tissues mobilize their folate
stores and return monoglutamyl folate to the liver.
This folate is released by the liver via the enterohepatic
cycle and distributed to the tissues that most require
it – in particular, those with actively proliferating
cells. Preferential uptake of folate by certain tissues
(e.g. placenta and choroid plexus) is made possible
by the presence of the folate receptor on their cellular
surfaces. The kidney plays its part in conserving
body folate by actively reabsorbing folate from the
glomerular fi ltrate. In addition, a pathway exists that
is capable of salvaging folate released from senescent

Uptake of 5-methyl-THF by sinusoidal membrane
vesicles isolated from human liver is an electroneutral
active transport process, which is pH-dependent, sodium-
independent and appears to involve co-transport
with hydrogen ions mediated by the reduced
folate carrier (Horne et al., 1993). This would require
a mechanism for maintaining a gradient of H+ across
the basolateral membrane, but how this is accomplished
is not known for certain. Sinusoidal membrane
vesicles isolated from rat hepatocytes contain a
Na+–H+ exchange system (Arias & Forgac, 1984) and
it can be speculated that the H+ could be conducted
along the membrane and interact with the carrier,
thereby generating a ‘localized’ proton gradient that
could energize active transport of 5-methyl-THF.

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