1.

Historically, nicotinic acid has been administered to patients with a variety of

disorders, often more for the dramatic skin reaction than proven curative powers. Its
most successful use is for the treatment of hyperlipidemia. The mechanisms of action
of high-dose nicotinic acid are unrelated to the formation of NAD(P) and unrelated to
the actions of nicotinamide. The main effect is a decrease in lipolysis in adipose tissue
due to an inhibition of adenylate cyclase activity. The resulting drop in cAMP levels
leads to the decreased mobilization of fatty acids, which is at least partially
responsible for a drop in VLDL formation by the liver and a subsequent drop in LDL
levels, although there may also be direct effects on liver lipid metabolism. Unlike
many treatments for hyperlipidemias, nicotinic acid also increases circulating levels
of HDL, the beneficial lipoprotein that removes cholesterol from vascular tissue. In
addition to the blood lipid effects, high-dose nicotinic acid causes a dramatic skin
flush of the face and upper trunk. All of these blood lipid effects appear to be due to
the binding of nicotinic acid to a highaffinity receptor, which is in turn linked to an
inhibitory G-protein, leading to decreased cAMP levels and inhibition of hormone-
sensitive lipase. This receptor is known as the niacin receptor or HM74A. It is termed
as an orphan receptor, as nicotinic acid is not thought to be its natural ligand, given
the unphysiologically high doses required to activate it. The skin flush, which is
mediated by prostaglandin formation, also appears to be caused by the binding of
nicotininic acid to HM74A, in this case, on the surface of macrophages. There are a
few drawbacks for using high levels of oral nicotinic acid. As mentioned earlier, the
short-term side effects may include vasodilation, burning or stinging sensations in the
face and hands, nausea, vomiting, and diarrhea. In the longer term, there may be
varying degrees of hyperpigmentation of the skin, abnormal glucose tolerance,
hyperuricemia, peptic ulcers, hepatomegaly, and jaundice. Newer versions of time-
release nicotinic acid have been reported to be safe and effective. It should be noted
that all drugs used in the treatment of hyperlipidemia have some side effects and
many of these problems can be managed through changes in dose. Interestingly,
nicotinic acid use for six years by patients with cardiovascular disease led to a
decrease in all-cause mortality measured 8 years after the drug use was discontinued.
A lipid-soluble derivative of nicotinic acid, which is active in lowering blood
cholesterol, and paradoxically, does not cause a skin flush reaction, is under
development by Niadyne Incorporated.
2. Interest in this area started with the finding that nicotinamide could prevent diabetes
induced by the b-cell toxins alloxan and streptozotocin. It was soon shown that the b-
cells were killed by excessive activation of PARP, which depleted cellular NAD
levels. Since nicotinamide is not a very high-affinity inhibitor of PARP, and cellular
levels tend to stay low due to active conversion to NAD, it seems likely that
protection in this model was due to the use of nicotinamide as a precursor of NAD
synthesis, although PARP-1 may have been partially inhibited. We have shown that
large oral doses of nicotinamide increase NAD and poly(ADP-ribose) levels in the
liver and more recently, in the bone marrow. Interestingly, animals protected from
chemically induced diabetes by nicotinamide all developed insulin producing b-cell
tumors, a form of cancer that is particularly lethal in humans. It is not surprising that
 cells rescued from NAD depletion due to extreme DNA damage, either through
inhibition of PARP or pharmacological support of NAD pools, would be at risk for
neoplastic growth because of the survival of cells with significant levels of DNA
damage. In humans, the onset of IDDM occurs spontaneously by immune recognition
of b-cell antigens. This is associated with leukocyte infiltration and the presence of
anti-islet cell antibodies in the serum. The spontaneous occurrence of IDDM is similar
in the nonobese diabetic (NOD) mouse. When nicotinamide is given to weaning NOD
mice, the onset of diabetic symptoms is prevented or delayed. As discussed in an
earlier section, catalytically active PARP-1 is now recognized as an inflammatory
mediator and as an inducer of apoptosis. Inhibition or genetic ablation of PARP-1 has
been shown to prevent diabetes in multiple low-dose streptozotocin and NOD animal
models. Recent studies more clearly implicate PARP-1 with the use of potent and
specific inhibitors.
3. Some foods contain thiamine-splitting enzymes (thiaminases). The threat to health
and life that can be posed by such enzymes is graphically illustrated by an ill-fated
expedition led by Burke and Wills, which set out to explore the center of Australia
from 1860 to 1861. During their return journey, the explorers were compelled to eat
inadequately cooked freshwater mussels and flour from Nardoo ferns. Both foods
contain high amounts of thiaminase, and four of five members of the expedition
perished from beriberi. Thiaminase type I occurs in the visceral organs of freshwater
fish, shellfish, ferns, certain seawater fish, and in some species of microorganisms.
Other species of microorganisms produce thiaminase type II, which is less common.
Both enzymes split thiamine into its two component rings, each by a different
mechanism. Thiaminase I acts by base-exchange between the thiazole ring of
thiamine and various nitrogenous bases; thiaminase II acts by simple hydrolysis.
When present in intact cells the thiaminases are inactive, but they become activated
when intracellular contents are liberated by cell membrane disruption. They can
destroy thiamine either during food storage, or during its preparation, or even within
the gastrointestinal tract. However, they can usually be inactivated by thorough
cooking, and are not a major problem in most human diets. Polyphenolic compounds
such as tannic acid, chlorogenic acid, and caffeic acid, which occur in tea, coffee,
betel nuts, and ferns, have also been reported to impair thiamine status in human
subjects. However, some of the research on these effects has later proved mis-leading,
either because there was interference by polyphenols with the thiochrome assay, or
because the products of polyphenol treatment of thiamine could be reconverted to
thiamine within the body, and the practical importance of heat-stable antithiamine
substances is controversial. In ruminant animals the rumen microflora may exert
complex effects on the thiamine supply to the host animal. Some species of rumen
bacteria synthesize and release thiamine, which can then be absorbed by the host
animal; others have surface enzymes that destroy it, especially at low pH. Severe
destruction of thiamine arises especially with high-concentration diets.
Cerebrocortical necrosis in ruminants is almost certainly caused by thiamine
deficiency whose origin is a thiaminase from the rumen bacteria. Bracken or
endophyte-infected fescue grass can antagonize thiamine, and high sulfate intakes can
 give rise to sulfite by reduction processes in the rumen; this can then destroy the
vitamin.
4. In the wake of contemporary interest in dietary antioxidants, one vitamin that is often
not appreciated sufficiently as a member of this category is riboflavin. Riboflavin has
little, if any, significant antioxidant action per se, but powerful antioxidant activity is
derived from its role as a precursor to FMN and FAD. A major protective role against
lipid peroxides is provided by the glutathione redox cycle . Glutathione peroxidase
breaks down reactive lipid peroxides. This enzyme requires GSH, which in turn is
regenerated from its oxidized form (GSSG) by the FAD-containing enzyme
glutathione reductase. Thus, riboflavin nutrition may be critical in regulating the rate
of inactivation of lipid peroxides. Diminished glu-tathione reductase activity would be
expected to lead to diminished concentrations of GSH that serve as substrate for
glutathione peroxidase and glutathione S-transferase, and therefore would limit the
rate of degradation of lipid peroxides and xenobiotic substances. Furthermore, the
reducing equivalents provided by NADPH, the other substrate required by glutathione
reductase, are primarily generated by an enzyme of the pentose monopho-sphate
shunt, glucose-6-phosphate dehydrogenase. Taniguchi and Hara, as well as Dutta et
al., have found that the activity of glucose-6-phosphate dehydrogenase is significantly
diminished during riboflavin deficiency. This observation provides an additional
mechanism to explain the diminished glutathione reductase activity in vivo during
riboflavin deficiency and the eventual decrease in antioxidant activity. There have
been reports (51,52) indicating that riboflavin deficiency is associated with
compromised oxidant defense and furthermore that supplementation of riboflavin and
its active analogs improves oxidant status. Riboflavin deficiency is associated with
increased hepatic lipid peroxidation and riboflavin supplementation limits this
process. In our laboratory, we have shown that feeding a riboflavin-deficient diet to
rats increases basal as well as stimulated lipid peroxidation.