University (Osaka, Japan), human pol κ by Dr. H. Ohmori and Dr. E. Ohashi of Kyoto

University (Kyoto, Japan), and human pol λ by Dr. O. Koiwai and Dr. N. Shimazaki of

Tokyo University of Science (Chiba, Japan).

This work was supported by Grant-in-aids (17380079 and 15658044) for Scientific

Research, MEXT (Ministry of Education, Culture, Sports, Science and Technology, Japan)

(Y. M., N. K. and K. M.). This work was also supported in part by a Grant-in-aid for KobeGakuin University Joint Research (A), and “Academic Frontier” Project for Private

Universities: matching fund subsidy from MEXT, 2006-2010, (Y. M. and H. Y.). Y. M.

acknowledges Grants-in-aid from the Nakashima Foundation (Japan).

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Inhibition of DNA Polymerase and Topoisomerase by Vitamin B6 19

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Takemura, M., Kato, N., Yoshida, H., & Sakaguchi, K. (2003) Pyridoxal 5'-phosphate

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[18] Mizushina, Y., Tanaka, N., Yagi, H., Kurosawa, T., Onoue, M., Seto, H., Horie, T.,

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acids selectively inhibit eukaryotic DNA polymerase activities in vitro. Biochim.

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[22] Oka, T., Komori, N., Kuwahata, M., Suzuki, I., Okada, M., & Natori, Y. (1994) Effect

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[23] Oka, T., Komori, N., Kuwahata, M., Sassa, T., Suzuki, I., Okada, M., & Natori, Y.

(1993) Vitamin B6 deficiency causes activation of RNA polymerase and general

enhancement of gene expression in rat liver. FEBS Lett., 331, 162-164.

[24] Molina, A., Oka, T., Munoz, S.M., Chikamori-Aoyama, M., Kuwahata, M., & Natori,

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In: Vitamin B: New Research ISBN 978-1-60021-782-1

Editor: Charlyn M. Elliot, pp. 21-38 © 2008 Nova Science Publishers, Inc.

Chapter II

THE CAUSES AND CONSEQUENCES OF

VITAMIN B-3 DEFICIENCY:

INSIGHTS FROM FIVE THOUSAND CASES

Harold D. Foster1

 and Abram Hoffer2

1

Department of Geography, University of Victoria, Canada;

2

Orthomolecular Vitamin Information Centre, Inc., Victoria, British Columbia, Canada.

ABSTRACT

Inadequacies of vitamin B-3 (niacin) can occur in at least six distinct, but

overlapping ways. Even when diet contains adequate niacin and there are no absorption

or storage problems, intake may be inadequate. This is because some individuals, for

genetic reasons, have abnormally high vitamin B-3 requirements that cannot be met by

the typical diet. As many as one-third of gene mutations result in the corresponding

enzyme having a decreased binding affinity for its coenzyme, producing a lower rate of

reaction. About fifty human genetic illnesses, caused by such defective enzymes,

therefore, can best be treated by very high doses of their corresponding coenzyme.

Several such genetic disorders have been linked to enzymes that have vitamin B-3 as

their coenzyme. These include elevated alcoholism and cancer risk, caused by defective

binding in aldehyde dehydrogenase and phenylketonuria II and hyperpharylalaninemia

that are associated with inadequate binding in dihydropteridine reductase.

There are two recently discovered types of niacin-responsive receptors, HM74A and

HM74B. HM74A is a high affinity receptor that mediates the stimulation of the synthesis

of prostaglandin by niacin. In parts of schizophrenics' brains, the protein for HM74A is

significantly decreased, confirming a niacin-related abnormality that results in very

elevated vitamin B-3 requirements. The simplest cases of niacin deficiency is caused by

diets that contain little or no vitamin B-3. Pellagra, for example, has traditionally been

diagnosed in patients who have been eating excessive quantities of maize, a food that

lacks easily available niacin. Vitamin B-3 deficiencies are also present in patients with

absorption and storage problems. Excessive consumption of sugars and starches, for

example, will deplete the body's supply of this vitamin, as will some antibiotics.

22 Harold D. Foster and Abram Hoffer

Addiction typically leads to niacin deficiency and can often be treated by taking high

doses of this vitamin. The breakdown of alcohol, for example, is vitamin B-3 dependent

because niacin is required as a coenzyme for one of the main enzymes involved,

aldehyde dehydrogenase. Since niacin is chemically similar to nicotine, the latter may

occupy niacin receptor sites. Certainly, high dose vitamin B-3 has helped many people

shed their addiction to nicotine.

Niacin deficiency also may be the result of excess oxidative stress, which causes an

abnormally high biochemical demand for this nutrient. It appears that multiple sclerosis,

amyotrophic lateral sclerosis, and Parkinson's disease involve the excessive breakdown

of dopamine, generating neurotoxins such as dopachrome. Vitamin B-3 can mitigate this

process but body stores are typically depleted by it. Similarly schizophrenics

overproduce adrenaline and its neurotoxic byproduct adrenochrome and other chrome

indoles. As a consequence, they become niacin depleted, a characteristic that is now

being used as a diagnostic symptom of this illness.

The ability to absorb nutrients typically declines with age. As a result, many vitamin

deficiencies, including niacin, are commonest in the elderly. These inadequacies are

reflected in cholesterol imbalances, cardiovascular disorders, stroke and arthritis, all of

which respond well to high dose niacin.

While optimum dosages vary, the literature, and Dr. Abram Hoffer's experience with

over 5,000 patients, suggest that required daily therapeutic intervention range from 10

mg in newly diagnosed cases of pellagra to 6 to 10 grams for cholesterol normalization,

and the treatment of cardiovascular disease and stroke.

Keywords: Binding affinity, HM74A, receptors, niacin, niacinamide, pellagra, alcoholism,

smoking, nicotinic acid, Parkinson's disease, multiple sclerosis, schizophrenia,

catecholamines, cholesterol.

INTRODUCTION

Identifying what constitutes a deficiency of vitamin B-3 is obviously an essential first

step in any discussion of its causes and consequences. So what represents an inadequacy of

this vitamin? Innocuous as this question may sound, it lies at the heart of a disagreement that

has divided medicine for over fifty years [1]. Many definitions of vitamins stress the very

small dosages that are required to maintain human and animal health. This is because

proponents of this viewpoint, referred to as the vitamins-as-prevention paradigm, believe that

vitamin deficiencies always cause obvious observable symptoms, such as the hemorrhaging

of scurvy seen in those with extreme vitamin C inadequacy, or the dementia occurring in

vitamin B-3 depleted patients with pellagra. It follows that if vitamins are needed only in

very small doses to prevent such deficiency diseases, large amounts are unnecessary, even

dangerous. This belief, that very small amounts of vitamins are all that are required to

maintain health, is enshrined in the concept of the recommended daily allowance (RDA),

established by law in many countries. Such dosages are typically the result of

recommendations by nutritionists, based on animal research. They do not rest on the results

from controlled studies, attempting to establish the vitamin intakes needed to establish

optimum human health.

The Causes and Consequences of Vitamin B-3 Deficiency… 23

There is no conflict over the efficacy of small vitamin doses for the prevention of

classical deficiency diseases. To illustrate, in regions where maize formed an excessive part

of the diet, pellagra was often endemic. However, this was not true of Central America where

maize was typically treated with alkali before it was cooked. Such lime solutions released

niacin from the tight biochemical bonds found in maize, so preventing pellagra. Indeed, the

addition of small amounts of nicotinamide to flour, the standard practice since 1942, has

greatly reduced the global incidence of classic pellagra [2]. In a similar manner, small doses

of vitamin C now prevent most scurvy, while low dosage amounts of vitamin D-3 are

protective against rickets.

The history of medicine, indeed of science as a whole, is one of paradigm shifts.

Scientific theories resemble architectural wonders. They are interesting to visit and

prestigious to be associated with. All too often, however, while they may appear to casual

observation to be sound and unassailable, termites are feasting deep within their foundations.

Anomalies, factors that the ruling theory and its supporters cannot adequately explain, are the

termites of science. As they breed and multiply, the infected theory weakens until it

eventually collapses. This process is now well underway within the vitamins-as-prevention

paradigm. Cheraskin [3], for example, has pointed out that although according to the

Recommended Dietary Allowance advised for the United States, 60 mg of vitamin C was the

accepted requirement of this nutrient, many conditions benefited from much more. The

research literature, for example, showed that one to three grams a day of this vitamin, taken

for several months, could correct infertility, strengthen blood vessels in diabetics, reduce the

severity of bipolar disease, extend male life expectancy by approximately six years, reduce

periodontal disease, and protect against ischemic heart disease, macular degeneration,

hypertension and cataracts. High doses of vitamin A and E seem to be beneficial in the

treatment of a similar wide variety of disorders. Cheraskin, of course, was supporting the

vitamins-as-drugs paradigm. The proponents of this viewpoint, known as orthomolecular

medicine, believe that vitamins, and indeed many other nutrients, taken regularly at dosages

far above the Recommended Dietary Allowances, can prevent, and in many cases cure, a

wide range of diseases and disorders [4-6]. This chapter examines whether this generalization

is true of vitamin B3.

CAUSES OF VITAMIN B-3 DEFICIENCIES

Genetic Causes

According to Ames and colleagues [7] "As many as one-third of mutations in a gene

result in the corresponding enzyme having an increased Michaelis constant, or Km (decreased

binding affinity) for a coenzyme, resulting in a lower rate of reaction". This means that there

are some 50 known human genetic diseases that occur because of defective, low binding

enzymes that can only be prevented or ameliorated by very high doses of their corresponding

coenzymes. Such elevated coenzyme doses may restore, or partially correct, depressed

enzymatic activity, so curing or mitigating these illnesses.

24 Harold D. Foster and Abram Hoffer

Several such polymorphisms result in lowered activity in enzymes that have a specific

vitamin as a cofactor. The resulting disorders can only be successfully treated by very high

doses of the appropriate vitamin, such as riboflavin, thiamine or folic acid. The mega-doses

of vitamins needed to treat such genetic diseases are levels that are a hundred to a thousand

or more fold higher than those as dietary reference intakes. To illustrate, if the enzyme

pyruvate decarboxylase is defective, causing Leigh disease and lactate and pyruvate buildup

in the serum, high dose thiamine is likely to be an effective treatment. Similarly, binding

defects in the enzyme protoporphyrinogen oxidase, causing variegate prophyria and

neuropsychiatric complications, including motor neuropathy are likely to respond to very

high doses of riboflavin.

Ames and coworkers identified a series of diseases and disorders, caused by genetic

mutations, that result in the corresponding enzyme having a decreased binding affinity for

niacin, its coenzyme. These health problems, therefore, can only be logically addressed by

treatment with high dose vitamin B-3. Such potentially defective enzymes, for example,

include aldehyde dehydrogenase, which increases the risk of alcoholism and cancer; glucose6-phosphate 1-dehyrogenase which is linked to hemolytic anemia and favism; and complex 1

(mitochondrial transfer RNA mutations) which is associated with complex 1 deficiency,

elevated blood lactate and pyruvate. Similarly, two other enzymes, dihydropteridine

reductase and long-chain-3-hydroxyacyl-CoA dehyrogenase, that can occur in low coenzyme

binding forms because of polymorphism, also use niacin as a cofactor. The former is

associated with phenylketonuria II, hyperphenylalaninemia and cognitive dysfunction, while

the latter has links to Beta-Oxidation defect, hypoglycemia, cardiomyopathy and sudden

death.

It follows, therefore, that for many of the 50 or so known genetic disorders, caused by

polymorphisms associated with decreased enzyme cofactor binding affinity, the vitamins-asdrug paradigm has to be correct. The only effective way to treat these health problems is with

very high dosages of cofactors, which in many cases are vitamins.