The Vitamins 141extrapolation, it has been assumed that retinol is also
teratogenic, although there is little evidence. In case–
control studies, intakes between 2400 μg/day and
3300 μg/day during pregnancy have been associated
with birth defects. Other studies have not demon-
strated any teratogenic effect at this level of intake,
and it has been suggested that the threshold plasma
concentration associated with teratogenic effects is
unlikely to be reached with intakes below 7500 μg/
day. Nevertheless, pregnant women are advised not to
consume more than 3000 μg/day (American Pediatric
Association recommendation) or 3300 μg (UK
Department of Health recommendation).
Interactions of vitamin A with drugs and
other nutrients
Historically, there was considerable confusion between
vitamins A and D, and for many years it was not clear
which acted in which system. By the 1950s it was
believed that the problem had been solved, with
clearly defi ned functions of vitamin A in vision, and
vitamin D in calcium homeostasis and bone develop-
ment. However, both have overlapping effects on a
number of systems, including bone metabolism and
immune system function. It is now known that this is
the result of formation of retinoid–vitamin D recep-
tor heterodimers, so that in some systems both are
required in appropriate amounts for normal regula-
tion of gene expression.
Chlorinated hydrocarbons, as contained in agricul-
tural pesticides, deplete liver retinol. Metabolites of
polychlorinated biphenyls bind to the thyroxine
binding site of transthyretin, and in doing so impair
the binding of RBP. As a result there is free RBP-
bound retinol in plasma, which is fi ltered at the glom-
erulus and hence lost in the urine. Habitual use of
barbiturates may also lead to defi ciency as a result of
induction of cytochrome P 450 , which catalyzes the
catabolism of retinol.
8.3 Vitamin D
Vitamin D is not strictly a vitamin, since it can be
synthesized in the skin, and indeed under most condi-
tions endogenous synthesis is the major source of the
vitamin: it is only when sunlight exposure is inade-
quate that a dietary source is required. Its main func-
tion is in the regulation of calcium absorption and
homeostasis; most of its actions are mediated by
nuclear receptors that regulate gene expression.
Defi ciency, leading to rickets in children and osteo-
malacia in adults, continues to be a problem in north-
ern latitudes, where sunlight exposure is poor.
There are relatively few sources of vitamin D, mainly
oily fi sh, with eggs, liver, and butter providing modest
amounts; fortifi ed milk, containing ergocalciferol, is
available in some countries. As a result, strict vegetar-
ians are especially at risk of defi ciency, especially in
northern latitudes with little sunlight exposure.
Although meat provides apparently negligible
quantities of vitamin D, it may be an important
source, since what is present is largely the fi nal active
metabolite, calcitriol, which is many times more
potent on a molar basis than is cholecalciferol.Vitamers and international units
The normal dietary form of vitamin D is cholecalcif-
erol (also known as calciol). This is also the com-
pound that is formed in the skin by ultraviolet (UV)
irradiation of 7-dehydrocholesterol. Some foods are
enriched or fortifi ed with (synthetic) ergocalciferol,
which undergoes the same metabolism as cholecalcif-
erol and has the same biological activity. Early studies
assigned the name vitamin D 1 to an impure mixture
of products derived from the irradiation of ergosterol;
when ergocalciferol was identifi ed it was called
vitamin D 2 , and when the physiological compound
was identifi ed as cholecalciferol it was called vita-
min D 3.
Like vitamin A, vitamin D was originally measured
in international units of biological activity before the
pure compound was isolated: 1 IU = 25 ng of chole-
calciferol; 1 μg of cholecalciferol = 40 IU.Absorption and metabolism
Vitamin D is absorbed in lipid micelles and incorpo-
rated into chylomicrons; therefore, people on a low-
fat diet will absorb little of such dietary vitamin D as
is available. Indeed, it is noteworthy that at the time
that rickets was a major public health problem in
Scotland, herrings (a rich source) were a signifi cant
part of the diet: it can only be assumed that the diet
was so low in fat that the absorption of the vitamin
was impaired.Synthesis of vitamin D in the skin
As shown in Figure 8.4, the steroid 7-dehydrocholes-
terol (an intermediate in the synthesis of cholesterol