Niacin: Nicotinic Acid and Nicotinamide

The human disease of pellagra was first described in
Spain by Casal in 1735 after the introduction of maize
into Europe from the Americas. In the 1920s, Goldberger
in the USA reported that pellagra and black
tongue in dogs responded to treatment with animal
protein and also to boiled protein-free extracts of
yeast. In 1937, Elvehjem found that the active component
in liver extracts used to successfully treat canine
black tongue was nicotinamide, and reports that nicotinic
acid cured pellagra soon followed.
Nicotinic acid and nicotinamide had been isolated
from the coenzymes now known as NAD and NADP
by 1934–1935; hence knowledge of their biochemical
roles in electron-transfer reactions preceded the discovery
of their nutritional signifi cance. By 1946, the
metabolism of dietary tryptophan to an active form
of the vitamin had been demonstrated.

In living tissues nicotinamide is the reactive moiety
of the coenzymes NAD and NADP. The structure of
NAD can be envisaged as the adenosine diphosphateribosyl
moiety, hereafter abbreviated as ADP-ribose,
attached covalently to nicotinamide through a β-Nglycosidic
linkage (Fig. 13.1). This linkage constitutes
a high-energy bond, the energy of which supplies the
driving force for various ADP-ribosylation reactions
(see Section 13.5.2). NAD glycohydrolases hydrolyse
the N-glycosidic linkage of NAD, yielding free ADPribose,
nicotinamide and a proton. Most cellular NAD
and NADP is stored in the cytoplasm, bound to protein
(Weiner & van Eys, 1983).

What is Pellagra , History of Pellagra

Pellagra
Pellagra was unknown in Europe until the 1730s,
when it was described in Spain by Gaspar Casal. It ap-
Historical events leading to the establishment of vitamins 5
peared at around the time that maize was brought to
Spain by Columbus from his voyages to America. The
disease spread from Spain into France and Italy and
eastward with the cultivation of maize and its use as
a staple foodstuff. Great epidemics occurred in North
Africa, especially in Egypt, later spreading to other
parts of Africa. It was widely held that pellagra was in
some way associated with spoiled maize and this led
investigators on a false trail looking for an infectious
or toxic agent. Pellagra fi rst became prominent in the
USA in 1907, affecting many poor families in the Midwest
and Southern States. Hundreds of thousands of
victims suffered ‘the 3-Ds’ – dermatitis, diarrhoea and
dementia. The widespread nature of the disease and
its association with poverty fuelled the belief that it
was infectious, perhaps spread by an insect vector.
By 1912, pellagra had become a matter of grave
national concern in the USA, with death rates up to
10 000 per year. In 1914 Joseph Goldberger, a bacteriologist
with the US Public Health Service, was assigned
the task of identifying the cause of pellagra. He noted
the association of the disease with poor diet and was
able to cure the disease and prevent recurrences in orphans
and hospital patients by adding liberal amounts
of milk and eggs to the institutional diets. Goldberger’s
next objective was to produce pellagra in previously
healthy human subjects by feeding them a pellagragenic
diet. The opportunity came in 1915 when a group
of twelve convicts volunteered to undergo the experiment
in return for pardons upon its completion. The
diet consisted of corn (maize) meal, grits, cornstarch,
wheat fl our, rice, cane syrup, sugar, sweet potatoes,
small amounts of turnip greens, cabbage and collards,
and a liberal portion of pork fat. After six months on
this diet, six of the eleven remaining volunteers had
developed pellagra. Goldberger concluded in his report
that ‘Pellagra may be prevented completely by a
suitable diet without intervention of any other factor,
hygienic or sanitary.’ He also considered the possibility
that the lack of a hitherto unknown factor in the diet
was responsible for the disease.

In the meantime, another group, the Thompson–
McFadden Commission, had tried to produce pellagra
in monkeys and baboons by injecting them with
blood, urine, cerebrospinal fl uid and tissue fi ltrates
from patients with pellagra. The results were entirely
negative and the Commission reported that infection
had not been demonstrated, no insect vector had been
found, and no relation between maize and the disease
had been noted. Even so, much emphasis was laid on
the poor sanitation of the communities investigated.
There was still a question mark over whether humans
could be infected with the disease.

It was Goldberger and 15 courageous colleagues
who fi nally put paid to the infection dogma. They
injected themselves with blood, swabbed their throats
with nasopharyngeal secretions and swallowed the excreta
and epidermal squames from patients severely
ill with pellagra. During the following six months not
one of these 16 scientists became ill.