Pellagra Research Articles

The effect of niacin deficiency on diethylnitrosamine‐induced hepatic poly(ADP‐ribose) levels and altered hepatic foci in the fischer‐344 rat

Poly(ADP-ribose) is synthesized on nuclear proteins in response to DNA damage and plays an important role in DNA repair. Niacin and tryptophan are dietary precursors to NAD+, which is the substrate for poly(ADP-ribose) synthesis. This study examined the influence of niacin status on poly(ADP-ribose) metabolism and carcinogenesis. Diets devoid of added niacin, with different levels of tryptophan, were used to produce moderate and severe niacin deficiencies in male Fischer-344 rats. Control rats were pair fed niacin-replete diets. After a 21-day feeding period, rats were injected with diethylnitrosamine (DEN) (Expt 1, 200 mg/kg ip; Expt 2, 100 mg/kg ip). In Experiment 1, blood and liver NAD+ and liver poly(ADP-ribose) were measured over the next 15 hours. Whereas blood and liver NAD+ were decreased by niacin deficiency, blood NAD+ was not affected by DEN. Liver NAD+ decreased significantly in response to DEN treatment in the pair-fed groups, but it did not change in the niacin-deficient groups. Unexpectedly, at 10 hours postinjection, liver poly(ADP-ribose) accumulation was greater (p < 0.05) in the niacin-deficient than in the pair-fed rats (n = 9), despite lower initial NAD+ levels and a lack of NAD+ disappearance in niacin-deficient livers. In Experiment 2, livers were examined for the presence of altered hepatic foci three months after DEN exposure. There were no significant differences in the percentage of liver occupied by foci between the niacin-deficient and pair-fed groups (n = 8). These results indicate that niacin-deficient rats were able to accumulate higher concentrations of hepatic poly(ADP-ribose) in response to DEN and did not show elevated susceptibility to initiation of altered hepatic foci.

Evaluating the role of niacin in human carcinogenesis

Our understanding of the role of ADP-ribose polymer metabolism in limiting carcinogenic events and the dependence of this metabolism on cellular NAD levels predicts that niacin deficiency leading to reduced NAD levels may enhance carcinogenesis. This prediction has led us to initiate studies to evaluate the potential of niacin as a preventive factor in human cancer. The first approach involves development of a method to assess biochemically niacin status in humans using intracellular NAD derived from whole blood, primarily erythrocytes, as the relevant marker of niacin status. We have shown that erythrocyte NAD content varies by as much as 12-fold within a population and can be modulated readily by supplementation. A second approach to testing this hypothesis involves understanding the relationship of dietary niacin, circulating levels of NAD precursors (nicotinamide and nicotinic acid) and NAD in target tissues for human cancer. Current analytical methods for quantification of plasma levels of nicotinic acid and nicotinamide following intake in the dietary range are not sufficient. Thus, we have developed a GC-MS method for the rapid, sensitive, and selective determination of both nicotinamide and nicotinic acid in plasma. These methods will now allow assessment of niacin metabolism in humans that could lead to a new understanding of niacin in prevention of cancer.

Conversion ratio of tryptophan to niacin in rats fed with a nicotinic acid-free, tryptophan-limiting diet.

The effects of amino acid composition on the conversion ratio of Trp to niacin in rats were investigated. The ratio in the group fed with a nicotinic acid-free, 9% casein-sucrose diet (basal diet) was 3.5%. This ratio was statistically decreased to 0.2% by the addition of 2% glycine, 0.078% L-threonine, and 0.2% L-cystine, and restored to 3.2% by the further addition of 0.1% tryptophan. From these results and our previous findings, it was considered that Trp imbalance might be a manifestation of niacin deficiency.

Dietary Niacin Deficiency Lowers Tissue Poly(ADP-Ribose) and NAD+ Concentrations in Fischer-344 Rats

Poly(ADP-ribose) is synthesized in response to DNA strand breaks, using NAD+ as substrate, and has been implicated in the process of DNA repair. Because NAD+ can be synthesized from niacin or tryptophan, both of these components must be manipulated to alter niacin status. Six dietary treatments were used, including niacin-deficient (ND) diets and niacin-replete (NR) diets consumed ad libitum and the NR diets pair-fed (PF) to the ND intake. The ND, NR and PF diets contained either 80 g casein + 50 g gelatin/kg diet (8-5 diets) or 70 g casein + 60 g gelatin/kg diet (7-6 diets) to control tryptophan content. The 8-5ND and 7-6ND diets induced mild and severe symptoms of niacin deficiency, respectively, over a 3-wk period in male weanling Fischer-344 rats. Food intake and weight gain were suppressed in both of the ND groups compared with their respective NR controls. Weight gain was not different between ND animals and their PF counterparts. At 3 wk, blood, liver, kidney, heart and lung NAD+ concentrations for both 8-5ND and 7-6ND animals were all significantly lower than those for their respective PF groups. In the groups fed the 8-5 diets, liver poly(ADP-ribose) was lower in the ND group (64% of PF), with no difference between the NR and PF groups. In rats fed the 7-6 diets, poly(ADP-ribose) levels were further decreased in the ND group (43% of PF), but food restriction also exerted an independent effect (PF levels were 46% of NR levels).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Dietary 6-Aminonicotinamide, an Antagonist of Nicotinamide, on the Metabolism of Tryptophan to Nicotinamide in Rats

It has been reported that pellagra is caused by abnormal metabolism of tryptophan, although it is generally believed that pellagra is caused by a deficiency of niacin. The administration of 6-aminonicotinamide (6-AN) to rats induces central nervous lesions being similar those seen in pellagra. So, we investigated the effects of 6-AN on the metabolism of tryptophan to nicotinamide. The threshold of the toxicity of 6-AN was around 0.001% when it was incorporated in the diet. In enzyme activities involved in the metabolism of tryptophan to nicotinamide, the activities of tryptophan oxygenase and aminocarboxymuconate-semialdehyde decarboxylase were greatly increased, while that of kynureninase was decreased by feeding of 6-AN diets. In enzymes involved in catabolism of nicotinamide, the activity of nicotinamide methyltransferase was increased and those of N1-methyl-2-pyridone-5-carboxamide (2-Py)- and N1-methyl-4-pyridone-3-carboxamide (4-Py)-forming N1-methylnicotinamide (MNA) oxidases were decreased by feed...

ACUTE ENCEPHALOPATHY DUE TO COEXISTENT NICOTINIC ACID AND THIAMINE DEFICIENCY

SUMMARY We report the case of an alcoholic woman with confusion, catatonia and extrapyramidal signs, who developed features of the Wernicke‐Korsakoff syndrome after treatment with intravenous high potency vitamins. We emphasise that this should arouse the suspicion of nicotinic acid deficiency even in the absence of gastrointestinal symptoms or skin lesions.

Niacin deficiency and cancer in women.

A new interest in the relationship between niacin and cancer has evolved from the discovery that the principal form of this vitamin, NAD, is consumed as a substrate in ADP-ribose transfer reactions. Poly(ADP-ribose) polymerase, an enzyme activated by DNA strand breaks, is the ADP-ribosyltransferase of greatest interest with regard to effects on the niacin status of cells since its Km for NAD is high, and its activity can deplete NAD. Studies of the consequences of DNA damage in cultured mouse and human cells as a function of niacin status have supported the hypothesis that niacin may be a protective factor that limits carcinogenic events. To test this hypothesis in humans, we used a biochemical method based on the observation that as niacin nutriture decreases, NAD readily declines and NADP remains relatively constant. This has been demonstrated in both fibroblasts and in whole blood from humans. Thus, we use "niacin number," (NAD/NAD+NADP) x 100% from whole blood, as a measure of niacin status. Healthy control subjects showed a mean niacin number of 62.8 +/- 3.0 compared to 64.0 for individuals on a niacin-controlled diet. Analyses of women in the Malmö Diet and Cancer Study showed a mean niacin number of 60.4 with a range of 44 to 75. The distribution of niacin status in this population was nongaussian, with an unpredictably large number of individuals having low values.

Research Note: Performance of Single Comb White Leghorn Pullets as Influenced by Niacin Supplementation from Zero to Six Weeks of Age and Subsequent Layer Performance

Two experiments were conducted using a total of 288 Hy-Line® W-36 day-old Single Comb White Leghorn (SCWL) pullets in each experiment. The pullets were randomly assigned to one of the six dietary treatments that consisted of 0, 1.5, 3.0, 6.0, 12.0, or 36.0 mg supplemental niacin/kg in a corn and soybean meal basal diet that contained 25.1 mg niacin/kg. Six replicates of eight pullets per replicate were used per treatment in each experiment. Feed and water were provided for ad libitum consumption. The pullets were housed in battery brooder pens with raised wire floors. Total feed consumption (FC), BW, BW gain, and feed efficiency (FE) were measured at 3 and 6 wk of age. Birds were observed daily for any signs of niacin deficiency. At the end of a 6-wk experimental period, the pullets that previously received the diets containing either 0 of 36.0 mg supplemental niacin/kg of diet were raised to sexual maturity (SM) and their age at SM, BW at 24 wk, and number of eggs per pullet through 36 wk were measured in both experiments.No differences (P<.05) in FC, BW, and FE were observed from 0 to 3 or 3 to 6 wk. None of the birds showed any signs of deficiency during the experimental period. No differences were observed in SM, number of eggs laid, and BW at 24 wk. It was concluded from these experiments that SCWL pullets do not require more than 25.1 mg/kg niacin furnished by the corn and soybean meal diet from 0 to 6 wk.

The urinary metabolites of niacin during the course of pellagra

The three main metabolites of niacin have been measured in urine of 10 Mozambican women living in refugee camps in Malawi and displaying clinical symptoms of pellagra. This study, in which a control group was included, showed that the ratio 6PYR/N1MN is well correlated to the occurrence of clinical symptoms of niacin deficiency and constitutes a reliable indicator of vitamin PP status in subjects at risk of this deficiency.

What is Pellagra?

What is Pellagra?

What is Pellagra?

What is Pellagra?

Effects of niacin deficiency on the relative turnover rates of proteins in various tissues of Japanese quail

1. 1. The effects of niacin deficiency on the relative turnover rates of proteins in various tissues of Japanese quail were investigated. 2. 2. The level of liver NAD was not affected by niacin deficiency whereas the level of pectoral muscle NAD was markedly reduced. 3. 3. In all dietary treatments the liver had the highest turnover rates of proteins, heart and brain had intermediate rates, and pectoral muscle had the lowest rates. 4. 4. Relative turnover rates of proteins in all tissues (particularly pectoral muscle) of the niacin deficient group were significantly higher than those of pair-fed control group, although there were no significant differences in turnover rate between pair-fed control and control groups. 5. 5. The high turnover rate of proteins in niacin deficiency was primarily attributed to enhanced degradation rate of proteins rather than enhanced synthesis rate of proteins. 6. 6. Optical density scanning (or densitometric) of water-soluble pectoral muscle proteins separated by isoelectric focusing revealed several additional minor protein bands between major protein bands in the niacin deficient group which were more pronounced in the acidic region of the gel. 7. 7. These results suggest that proteins with a low pI value in pectoral muscle of the niacin deficient animal are highly sensitive to protein degradation.

Kava-induced dermopathy: a niacin deficiency?

Heavy chronic consumption of kava ( Piper methysticum) is associated with a pellagroid dermopathy that has been attributed to niacin deficiency. Over 200 male kava drinkers in the Tonga Islands were interviewed and examined regarding the characteristic skin changes. A scaly rash suggestive of ichthyosis and eye irritation were present in some heavy kava drinkers. 29 kava drinkers with prominent skin changes were randomised to receive either 100 mg oral nicotinamide or placebo daily for three weeks. Skin examinations and photographs showed clinical improvement in 5/15 of the nicotinamide group and 5/14 of the placebo group. These data, along with history and physical examination findings, suggest that niacin deficiency is not responsible for the rash, which is more characteristic of an acquired ichthyosis.

Biochemical Markers for Assessment of Niacin Status in Young Men: Levels of Erythrocyte Niacin Coenzymes and Plasma Tryptophan

Seven male subjects housed in a controlled metabolic unit for 80 d were fed diets containing amounts of niacin and tryptophan ranging from 6.1 to 32 niacin equivalents (NE) per day. Erythrocyte nicotinamide adenine dinucleotide (NAD) and nicotinamide nucleotide phosphate (NADP), activity of nicotinic acid mononucleotide phosphoribosyltransferase (NMNPRT), plasma tryptophan levels and the urinary excretion of organic acids were measured during dietary periods of low (6.1 or 10.1), adequate (19) and high (25 or 32) NE intake. With both low NE diets, NAD levels in erythrocytes decreased by approximately 70% and increased during repletion with an adequate NE diet. NADP levels remained relatively unchanged. Plasma tryptophan levels decreased by 40% and 10% in subjects ingesting diets of 6.1 and 10.1 NE/d, respectively. A daily 7.8-g leucine supplement during repletion was not associated with changes in plasma tryptophan levels or erythrocyte NAD and NADP levels at the end of the period. No changes in NMNPRT activity or organic acid excretion were found during the study. The results indicate that the erythrocyte NAD level may serve as a sensitive indicator for the assessment of niacin status. Also, a niacin index, the ratio of erythrocyte NAD to NADP, below 1.0 may identify subjects at risk of developing a niacin deficiency.

Virgil Sydenstricker: special reference to niacin deficiency encephalopathy.

Virgil Sydenstricker was a member of a notable American family which included authoress Pearl S. Buck and the eminent epidemiologist Edgar Sydenstricker. Dr. Sydenstricker's contributions in the fields of hematology and nutritional disease are legion. His landmark work in sickle cell anemia characterized a definite symptom complex with specific hematologic findings and inheritance pattern. He wrote on the complications of malnutrition and attempted to delineate the specific effects of individual nutritional factors. Dr. Sydenstricker and his associate H. M. Cleckley first described the syndrome of niacin deficiency encephalopathy. Today, the syndrome is still occasionally reported. Niacin deficiency should be considered when unexplained acute confusional states or neurologic deficits occur in the setting of malnutrition, antituberculous drug use, or chronic partial nutritional deficiency with acute increase in metabolic demand.

Water-soluble vitamins in cancer patients on parenteral nutrition: a prospective study.

Forty-three patients with mild weight loss were studied prospectively to determine whether the parenteral water-soluble vitamin doses in a commercially available preparation (MVI concentrate; USV Laboratories, Tarrytown, NY) maintained serum, red blood cell (RBC), and urinary concentrations of water-soluble vitamins in stressed cancer patients receiving total parenteral nutrition (TPN). Patients were divided into three groups: (1) oral diet, no intravenous vitamins given; (2) TPN plus 5 ml MVI; and (3) TPN plus 10 ml MVI. Vitamins C, B1, B2, B3, B6, and niacin were measured initially and weekly during a 6-week study period. Caloric and nitrogen balances were quantified. Most of the patients in all three groups had normal blood or urine levels of all water-soluble vitamins. No clinical evidence of vitamin deficiency or MVI toxicity was detected. The recommended parenteral dosages of vitamin C (100 mg/day) and B3 (15 mg/day) provided measurably adequate levels in all patients. Levels of vitamins B1, B2, B6, and niacin that were less than the normal range were noted in 4-40% of patients receiving the recommended daily dosages of 3 mg, 3.6 mg, 4 mg, and 40 mg, respectively. These deficiencies appeared to improve in group III patients who received twice the recommended parenteral vitamin dosages, although they did not completely disappear. Niacin deficiency appeared to be the most prevalent, occurring in 40% of patients studied. Since intravenous doses of B1, B2, B6, and niacin are safe and well tolerated, it appears that increased daily amounts of these vitamins should be given to cancer patients on parenteral nutrition.

Pellagra

Pellagra

Free radicals in the pathogenesis of kwashiorkor.

The skeletal spectre of the marasmic child clearly results from a lack of intake of the bulk nutrients. It can be easily and consistently reproduced in any convenient species of experimental animal. In stark contrast, the other major form of malnutrition, kwashiorkor, has only once been convincingly reproduced in experimental animals. Coward & Whitehead (1972) produced oedema, fatty liver, skin lesions, hair discoloration and friability, hypoproteinaemia and mental changes in baboons by feeding the animals exactly the same diets that children with kwashiorkor received in Uganda. The authors demonstrated that the syndrome could be reproduced experimentally but made no attempt to discover the factor or factors in the diet responsible for the disease. In other studies the individual features of kwashiorkor had been singly and inconsistently reproduced in animals using a whole variety of, often extreme, experimental manipulations. The conditions necessary to give a ‘model’ for kwashiorkor oedema, for instance, are quite different from those used to give experimental fatty liver or hair discoloration. Why should the kwashiorkor syndrome be so difficult to reproduce experimentally I Why have the applied programmes designed to prevent kwashiorkor been so uniformly unsuccessful? The obvious first answer to be considered is that all the hypotheses that have been proposed, tested experimentally and used as the conceptual framework for the applied programmes, are incorrect. Certainly the extant hypotheses of protein deficiency (Williams, I 935)’ niacin deficiency (Gillman & Gillman, 195 I), antidiurectic-hormone-like action of free ferritin (Srikantia, 1958), dysadaptation to protein deficient stress (Gopalan, 1968), hormonal dysadaptation (Whitehead, 1979), or aflatoxin intoxication (Hendrickse, 1984), do not adequately explain more than a few of the features of kwashiorkor listed in Table I. These features must all be reconciled in any unifying hypothesis. Recently we have proposed that kwashiorkor results from an imbalance between the production of free radicals and their safe disposal (Golden, 1985). It is the purpose of the present paper to examine the evidence for such a hypothesis. The hypothesis, illustrated in Fig. I, states that in kwashiorkor, various noxae are imposed on the subject. These noxae produce free-radical-mediated lipid peroxides and toxic carbonyls. Under normal metabolic and nutritional

Effect of niacin and niacin-tryptophan deficiency on pancreatic acinar cell function in rats in vitro

To determine the effect of niacin deficiency on pancreas, rats were fed a standard rat chow ad libitum or an equal amount of a niacin-deficient or niacin-sufficient diet in the first experiment, or of a niacin-tryptophan-deficient or niacin-tryptophan-sufficient diet in the second experiment. Niacin deficiency decreased tissue chymotrypsinogen and trypsinogen content; amylase, chymotrypsinogen, and trypsinogen concentration; and basal secretion of total protein. Niacin-tryptophan deficiency decreased body weight, pancreas weight, and content of DNA, protein, amylase, lipase, chymotrypsinogen, and trypsinogen. Secretion of amylase and trypsinogen was increased. These studies indicate that niacin and niacin-tryptophan deficiency alter digestive-enzyme content and secretion, probably due to metabolic abberrations that result in an altered redox state of the acinar cell.

Effects of Niacin Deficiency on Growth and Development of the Mediterranean Fruit Fly (Diptera: Tephritidae)1

Deletion of niacin from an artificial diet developed for the Mediterranean fruit fly, Ceratitis capitata (Wiedemann), resulted in high larval mortality, reduced pupation, longer time to pupation, and low adult emergence. Addition of niacin antagonists to complete diets had no effect at the concentration tested. Niacin deficiency could not be overcome by addition of tryptophan to the diet. However, when either niacinamide or nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) replaced niacin, growth and development appeared normal. The importance of both niacin and niacinamide as precursors to the pyridine nucleotides supports the notion that physiological processes involving these nucleotides may be affected.