Dietary Sources High Intakes and Antimetabolites

As can be seen from Table 1, different types of foods differ considerably, not only in their total contribution to nicotinic acid equivalents, but also in the ratio of the contribution from preformed niacin and from tryptophan. In a typical Western diet, it has been calculated that if the 60 mg tryptophan = 1 mg niacin formula is applied, then preformed niacin provides about 50% of the niacin supply in the diet. In practice it seems possible for all of the niacin requirement to be provided by dietary tryptophan in Western diets. As is the case for the other B vitamins, meat, poultry, and fish are excellent sources of niacin equivalents, followed by dairy and grain products, but as noted above, certain grains such as maize, and whole highly polished rice, can be very poor sources and may be associated with clinical deficiency if the diets are otherwise poor and monotonous.

In recent years, both nicotinamide and nicotinic acid have been proposed and tested for possibly useful pharmacological properties at high intake levels. This new phase of interest in the vitamin has, in turn, raised concerns about the possible side effects of high intakes, and the definition of maximum safe intakes.

The greatest interest, in pharmacological terms, has been centered around nicotinic acid, which has been shown to have marked antihyperlipidemic properties at daily doses of 2-6 g. Nicotinamide does not share this particular pharmacological activity. Large doses of nicotinic acid reduce the mobilization of fatty acids from adipose tissue by inhibiting the breakdown of triacylglycerols through lipolysis. They also inhibit hepatic triacylglycerol synthesis, thus limiting the assembly and secretion of very low-density lipoproteins from the liver and reducing serum cholesterol levels. Large doses of nicotinic acid ameliorate certain risk factors for cardiovascular disease: for instance they increase circulating high-density lipoprotein levels. The ratio of HDL2 to HDL3 is increased by nicotinic acid; there is a reduced rate of synthesis of apolipoprotein A-II and a transfer of some apolipoprotein A-I from HDL3 to HDL2. These changes are all considered potentially beneficial in reducing the risk of cardiovascular disease. If given intravenously, large doses of nicotinic acid can, however, produce side effects such as temporary vasodilatation and hypotension. Other side effects can include nausea, vomiting, diarrhea and general gastrointestinal disturbance, headache, fatigue, difficulty in focusing, skin discoloration, dry hair, sore throat, etc. A large trial for secondary prevention of myocardial infarction, with a 15 year period of follow-up, produced convincing evidence for moderate but significant protection against mortality, which was attributed either to the cholesterol-lowering effect or an early effect on nonfatal reinfarction, or both. Nicotinic acid is still the treatment of choice for some classes of high-risk hyperlipidemic patients, although newer drugs may have fewer side effects and therefore be preferred.

The potential benefits of the lipid-lowering effects of nicotinic acid have to be considered in the light of possibly toxic effects, particularly for the liver. These may manifest as jaundice, changes in liver function tests, changes in carbohydrate tolerance, and changes in uric acid metabolism including hyper-uricemia. There may also be accompanying ultrastructural changes. Hyperuricemia may result from effects on intestinal bacteria and enzymes, and from effects on renal tubular function. Such toxic effects are especially severe if sustained release preparations of nicotinic acid are used.

Nicotinamide does not share with nicotinic acid these effects on lipid metabolism or the associated toxicity. However, it has been shown to be an inhibitor of poly (ADP ribose) synthetase in pancreatic fl cells in animal studies. A high-risk group of children aged 5-8 years in New Zealand given large doses of nicotinamide daily for up to 4.2 years had only half the predicted incidence of insulin-dependent diabetes.

Other claims for megadoses of nicotinic acid or nicotinamide, such as the claim that abnormalities associated with schizophrenia, Down's syndrome, hyperactivity in children, etc. can be reduced, have so far failed to win general acceptance. Clearly nia-cin deficiency or dependency can exacerbate some types of mental illness such as depression or dementia. There have been a number of attempts to treat depression with tryptophan or niacin, or both, on the basis that the correction of depressed brain levels of serotonin would be advantageous. However, these have met with only limited success. Schizophrenics have been treated with nicotinic acid on the basis that their synthesis of NAD is impaired in some parts of the brain, and that the formation of hallucinogenic substances such as methylated indoles may be controlled.

There are various medical conditions and drug interactions that can increase the requirement for niacin. Examples are: Hartnup disease, in which tryp-tophan transport in the intestine and kidney is impaired; carcinoid syndrome, in which tryptophan turnover is increased; and isoniazid treatment, which causes B6 depletion and hence interference with nia-cin formation from tryptophan. Hartnup disease (the name of the first patient being Hartnup) is a rare genetic disease in which the conversion of tryptophan to niacin is reduced, partly as a result of impaired tryptophan absorption. Affected subjects exhibit the classical skin and neurological lesions of pellagra, which can be alleviated by prolonged treatment with niacin. Another genetic disease which may respond to niacin supplements is Fredrikson type I familial hypercholesterolemia; nicotinic acid is effective in reducing the raised blood cholesterol levels associated with this abnormality.

There are several analogs and antimetabolites of niacin that are of potential use or metabolic interest. The closely related isoniazid is commonly used for treatment of tuberculosis; indeed, nicotin-amide itself has been used for that purpose. Nicoti-nic acid diethylamide ('nikethamide') is used as a stimulant in cases of central nervous system depression after poisoning, trauma or collapse. Possible antineoplastic analogs include 6-dimethyl-aminonicotinamide and 6-aminonicotinamide; however, the latter is also highly teratogenic. These latter compounds inhibit several key enzymes whose substrates are NAD or NADP, by being converted in vivo to analogs of these coenzymes. The compound 3-acetyl pyridine, which also forms an analog of NAD, can have either antagonistic or niacin-replacing properties, depending on the dose used. Commonly used drugs such as metronidazole are also niacin antagonists.

See also: Bioavailability. Energy: Metabolism. Hyperlipidemia: Overview; Nutritional Management. Riboflavin. Vitamin B6.

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