176 Introduction to Human Nutrition
much of the [^3 H]-thymidine after incubation with
dUMP as they do without preincubation.
Either a primary defi ciency of folic acid or func-
tional defi ciency secondary to vitamin B 12 defi ciency
will have the same effect. In folate defi ciency, addition
of any biologically active form of folate, but not
vitamin B 12 , will normalize the dUMP suppression of
[^3 H]-thymidine incorporation. In vitamin B 12 defi -
ciency, addition of vitamin B 12 or methylene-
tetrahydrofolate, but not methyl-tetrahydrofolate,
will normalize dUMP suppression.
Drug–nutrient interactions of folate
Several folate antimetabolites are used clinically, as
cancer chemotherapy (e.g., methotrexate), and as
antibacterial (trimethoprim) and antimalarial (pyri-
methamine) agents. Drugs such as trimethoprim and
pyrimethamine act by inhibiting dihydrofolate reduc-
tase, and they owe their clinical usefulness to a con-
siderably higher affi nity for the dihydrofolate reduc-
tase of the target organism than the human enzyme;
nevertheless, prolonged use can result in folate
defi ciency.
A number of anticonvulsants used in the treatment
of epilepsy, including diphenylhydantoin (phenytoin),
and sometimes phenobarbital and primidone, can
also cause folate defi ciency. Although overt megalo-
blastic anemia affects only some 0.75% of treated
epileptics, there is some degree of macrocytosis in
40%. The megaloblastosis responds to folic acid sup-
plements, but in about 50% of such patients treated
with relatively high supplements for 1–3 years there
is an increase in the frequency of epileptic attacks.
Folate toxicity
There is some evidence that folate supplements in
excess of 400 μg/day may impair zinc absorption. In
addition, there are two potential problems that have
to be considered when advocating either widespread
use of folate supplements or enrichment of foods
with folate for protection against neural tube defect
and possibly cardiovascular disease and cancer.
● Folate supplements will mask the megaloblastic
anemia of vitamin B 12 defi ciency, so that the pre-
senting sign is irreversible nerve damage. This is
especially a problem for older people, who may
suffer impaired absorption of vitamin B 12 as a result
of atrophic gastritis. This problem might be over-
come by adding vitamin B 12 to foods as well as
folate. Whereas gastric acid is essential for the
release of vitamin B 12 bound to dietary proteins,
crystalline vitamin B 12 used in food enrichment is
free to bind to cobalophilin without the need for
gastric acid.
● Antagonism between folic acid and the anticonvul-
sants used in the treatment of epilepsy is part of
their mechanism of action; about 2% of the popu-
lation have (drug-controlled) epilepsy. Relatively
large supplements of folic acid (in excess of 1000 μg/
day) may antagonize the benefi cial effects of some
anticonvulsants and may lead to an increase in the
frequency of epileptic attacks. If enrichment of a
food such as bread with folate is to provide 400 μg/
day to those who eat little bread, those who eat a
relatively large amount may well have an intake in
excess of 1000 μg/day. There is, however, no evi-
dence of a signifi cant problem in countries where
enrichment of fl our has been mandatory for some
years.8.12 Biotin
Biotin was originally discovered as part of the complex
called bios, which promoted the growth of yeast and,
separately, as vitamin H, the protective or curative
factor in “egg white injury,” the disease caused in
humans and experimental animals being fed diets
containing large amounts of uncooked egg white. The
structures of biotin, biocytin, and carboxy-biocytin
(the active metabolic intermediate) are shown in
Figure 8.17.
Biotin is widely distributed in many foods. It is
synthesized by intestinal fl ora, and in balance studies
the total output of biotin in urine plus feces is three
to six times greater than the intake, refl ecting bacterial
synthesis. It is not known to what extent this is avail-
able to the host.Absorption and metabolism of biotin
Most biotin in foods is present as biocytin (ε-amino-
biotinyllysine), which is released on proteolysis, then
hydrolyzed by biotinidase in the pancreatic juice and
intestinal mucosal secretions, to yield free biotin. The
extent to which bound biotin in foods is biologically
available is not known.
Free biotin is absorbed from the small intestine by
active transport. Biotin circulates in the bloodstream