Niacin Deficiency
In human pellagra the deficiency is generally not one of niacin alone. The response of pellagrins to niacin treatment is a partial one. The cheilosis, if present, may not be altered, and neurological symptoms may remain. The term pellagra can scarcely be thought of as indicating a specific set of symptoms. In other words, the symptoms in one individual case may be very different from those of another, and the response to various members of the B complex may show little resemblance in the two cases.
Variations in the pellagrous syndrome seen in different parts of the world are well known.
Other B vitamins and general inanition are certainly involved. The symptom's generally associated with the condition are (a) dermatitis, accompanied by pigmentation (exaggerated by sunlight), and erythema of the tongue, which often becomes smooth and atrophic; (b) nervous lesions, especially in late stages, which involve varying regions of the cerebrum and spinal cord fibers (myelin degeneration); (c) gastrointestinal lesions characterized by cyst formation in the colon and atrophy in the later stages; and Cd) mottled liver with fatty degeneration. The nervous symptoms especially are thought to arise from a deficiency other than that of niacin. They are similar, except in distribution, to the findings in thiamine deficiency. Studies of various tongue lesions in man have led to the conclusion that other members of the B complex are often deficient and that niacin frequently has little or no beneficial effect.
Goldsmith and others, however, produced clinical pellegra symptoms in humans and reported that all the lesions responded to nicotinamide or to tryptophan. Horwitt and others studied a group of men on low niacin and tryptophan intake over long periods of time. Other men received the same diet with supplements of the vitamin and tryptophan.
Physical changes other than those attributed to the accompanying riboflavin deficiency were not found in either group. No cutaneous lesions such as found in pellegra were noted.
It was found from the studies on urinary excretion of niacin metabolites that the amount of )«!-methylnicotinamide in the urine correlated best with the niacin and tryptophan content of the diet. Pellegra is especially frequent among peoples eating corn as a large part of the diet. In some degree this may be explained by the low tryptophan content of corn, although there is more to the story than is known at present. This problem is discussed in some detail by Goldsmith. The flushing syndrome is well known in human beings taking nicotinic acid either by mouth or parenterally.
The amide does not produce these symptoms. It is the latter compound that is found in natural sources of the vitamin. Some individuals flush with only a few milligrams of niacin, while others are able to take 100 mg without untoward effects. Many people flush on the intravenous administration of 5 or 10 mg of niacin. In animals experimental niacin deficiency is readily produced. Blacktongue in the dog has been studied intensively, and this syndrome has a close resemblance to that seen in humans, especially with regard to the oral cavity. Special dietary precautions are required in rats, for example, to show disorders which respond to niacin administration. Diets high in corn or otherwise low in tryptophan predispose to this condition. Corn is low in tryptophan, and it has been suggested that this amino acid is required in the gastrointestinal tract for bacterial synthesis of niacin-an important source of the vitamin in this species.
The addition of tryptophan-containing protein, or the amino acid, k the diet of rats cures or prevents the symptoms. It is now established that in some species tryptophan can substitute in the diet for niacin. The conversion of the amino acid to the vitamin has been studied in great detail. A number of compounds arising in the body from tryptophan metabolism have b~en isolated. Several of these have niacin activity in rats and support growth in neurospora. The following scheme has been proposed by Hayaishi and others for the conversion of tryptophan into niacin in mammalian liver.
Tryptophan ---> kynurenine ---> 3-hydroxykynurenine ---> 3-hydroxyanthranilic acid ---> 2-acroleyl-3-aminofumaric acid ---> quinolinic acid --> nicotinic acid (niacin)
Actually the quinolinic acid is converted to a nucleotide structure and then loses CO2 to become niacin ribonucleotide, which is phosphorylated by ATP yielding deamido DNP. This reacts with glutamine forming DPN and thus the series of events con£titutes the synthesis of the coenzyme from the amino acid.
The last steps are identical with the conversion of niacin into the coenzyme. The structures of these compounds can be found under tryptophan metabolism. In the rat the site of this transformation was thought to be the gastrointestinal tract. However, it is obvious now that other tissues participate in catalyzing this reaction. Henderson and Hanks removed the gastrointestinal tracts of rats from the duodenum to the anus and then gave them sterile mixtures of amino acids, carbohydrate, salts, etc., by subcutaneous injection.
Some of the animals (and unoperated controls) were given tryptophan in the food mixture.
Analyses demonstrated the presence of increased amounts of Nl-methylnicotinamide. "free," and total niacin in the urine of both control and enterectomized rats given the amino acid. The N-methyl derivative is known to be formed from niacin in the body. Handley and Bond offered a clear-cut demonstration of this by feeding rats niacin containing C,a in the carboxyl group. Results of examination of the isolated and purified N-methylnicotinamide from the urine indicated that over 95 per cent of this compound had arisen from the administered niacin. These results establish the activity of body tissues other than the gastrointestinal tract in the conversion of this amino acid to the vitamin. Serum cholesterol is lowered in humans after the ingestion of large doses of nicotinic acid; the amide is without effect. In young adults the basal metabolism is increased also.
The mechanism by which blood cholesterol is lowered has not been resolved. In rats the blood levels of cholesterol are also decreased by massive intakes (up to 4 per cent of the diet). This effect was attributed to the great demand for methyl groups used in nicotinic acid detoxication, with a resulting decreased cholesterol synthesis.
