Mechanisms of the Pellagragenic Effect of Leucine: Stimulation of Hepatic Tryptophan Oxidation by Administration of Branched-Chain Amino Acids to Healthy Human Volunteers and the Role of Plasma Free Tryptophan and Total Kynurenines

Badawy, Abdulla A.-B.; Lake, Sarah L.; Dougherty, Donald M.

doi:10.4137/ijtr.s18231

Cited by 26 publications

(40 citation statements)

References 38 publications

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“…In the present study, kynurenine, which contributed significantly to the observed separation between the treatment groups, was decreased in the DIL cows as compared with the DIG and SAL cows at both time-points. The effects of high Leu-diet on Trp oxidation along the kynurenine pathway were documented in laboratory animal and in human studies [45]. Interestingly, in the present study, the lower plasma kynurenine was accompanied with the lower plasma Trp in the DIL cows as compared with the DIG and SAL cows at 50 min after the infusion.…”

Section: Discussionsupporting

confidence: 57%

Plasma amino acids and metabolic profiling of dairy cows in response to a bolus duodenal infusion of leucine

et al. 2017

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Leucine (Leu), one of the three branch chain amino acids, acts as a signaling molecule in the regulation of overall amino acid (AA) and protein metabolism. Leucine is also considered to be a potent stimulus for the secretion of insulin from pancreatice β-cells. Our objective was to study the effects of a duodenal bolus infusion of Leu on insulin and glucagon secretion, on plasma AA concentrations, and to do a metabolomic profiling of dairy cows as compared to infusions with either glucose or saline. Six duodenum-fistulated Holstein cows were studied in a replicated 3 × 3 Latin square design with 3 periods of 7 days, in which the treatments were applied at the end of each period. The treatments were duodenal bolus infusions of Leu (DIL; 0.15 g/kg body weight), glucose (DIG; at Leu equimolar dosage) or saline (SAL). On the day of infusion, the treatments were duodenally infused after 5 h of fasting. Blood samples were collected at -15, 0, 10, 20, 30, 40, 50, 60, 75, 90, 120, 180, 210, 240 and 300 min relative to the start of infusion. Blood plasma was assayed for concentrations of insulin, glucagon, glucose and AA. The metabolome was also characterized in selected plasma samples (i.e. from 0, 50, and 120 min relative to the infusion). Body weight, feed intake, milk yield and milk composition were recorded throughout the experiment. The Leu infusion resulted in significant increases of Leu in plasma reaching 20 and 15-fold greater values than that in DIG and SAL, respectively. The elevation of plasma Leu concentrations after the infusion led to a significant decrease (P<0.05) in the plasma concentrations of isoleucine, valine, glycine, and alanine. In addition, the mean concentrations of lysine, methionine, phenylalanine, proline, serine, taurine, threonine, and asparagine across all time-points in plasma of DIL cows were reduced (P<0.05) compared with the other groups. In contrast to the working hypothesis about an insulinotropic effect of Leu, the circulating concentrations of insulin were not affected by Leu. In DIG, insulin and glucose concentrations peaked at 30–40 and 40–50 min after the infusion, respectively. Insulin concentrations were greater (P<0.05) from 30–40 min in DIG than DIL and SAL, and glucose was elevated in DIG over DIL and SAL from 30–75 min and 40–50 min, respectively. Multivariate metabolomics data analysis (principal component analysis and partial least squares discriminant analysis) revealed a clear separation when the DIL cows were compared with the DIG and SAL cows at 50 and 120 min after the infusion. By using this analysis, several metabolites, mainly acylcarnitines, methionine sulfoxide and components from the kynurenine pathway were identified as the most relevant for separating the treatment groups. These results suggest that Leu regulates the plasma concentrations of branched-chain AA, and other AA, apparently by stimulating their influx into the cells from the circulation. A single-dose duodenal infusion of Leu did not elicit an apparent insulin response, but affected multiple inte...

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Section: Discussionsupporting

confidence: 57%

Plasma amino acids and metabolic profiling of dairy cows in response to a bolus duodenal infusion of leucine

et al. 2017

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“…However, irrespective of whether or not enzyme activities are enhanced, the observed increases in K metabolites can be explained simply by the increased flux of Trp down the pathway following its release from plasma albumin binding being the initiating event. Free Trp is a major determinant of this flux ( Smith and Pogson, 1980 ; Badawy et al , 2014 ). The major route of kynurenine metabolism is through hydroxylation to 3-HK followed by hydrolysis of the latter to 3-HAA, with transamination being a minor route, because the k m 's for substrates of kynurenine hydroxylase and kynureninase are much lower than those for the aminotransferase ( Bender, 1983 ).…”

Section: Discussionmentioning

confidence: 99%

Elevation of Kynurenine Metabolites in Rat Liver and Serum: A Potential Additional Mechanism of the Alcohol Aversive and Anti-cancer Effects of Disulfiram?

Badawy

Bano

2015

Alcohol and Alcoholism

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AimsThe tryptophan metabolites 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA) inhibit the liver mitochondrial low Km aldehyde dehydrogenase and possess alcohol-aversive and immunosuppressant properties. As the disulfiram (DS) metabolite carbon disulphide activates enzymes forming 3-HK and 3-HAA, we investigated if repeated disulfiram treatment increases the hepatic and serum levels of these 2 metabolites.MethodsLivers and sera of male Wistar rats were analysed for tryptophan and kynurenine metabolites after repeated DS treatment for 7 days.ResultsDS increased liver and serum [3-HK] and [3-HAA] possibly by increasing the flux of tryptophan down the hepatic kynurenine pathway and activation of kynurenine hydroxylase and kynureninase.ConclusionsWe provisionally suggest that elevation of some kynurenine metabolites may be an additional mechanism of the alcohol-aversive and anticancer effects of disulfiram.

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“…The tryptophan levels do, however, vary in different types of maize and are influenced by environmental conditions. 70 In addition, maize contains considerable amounts of the amino acid leucine 74 which, when present in high concentrations, interferes with de novo synthesis of niacin from tryptophan by inhibiting quinolinate phosphoribosyl transferase and, in addition, lowers the body's tryptophan levels 7 . Preliminary indications are that leucine in itself could exacerbate the mental derangements associated with pellagra.…”

Section: Pellagra and Maizementioning

confidence: 99%

“…6 Several factors may have pellagragenic effects, either through their influence on the absorption of niacin and/or tryptophan, or through their effects on the conversion of tryptophan to niacin. These factors include excessive leucine intake 7 , chronic alcoholism 1,2 , antituberculosis drugs 8 , immunosuppressive drugs 9 , eating disorders and a variety of gastrointestinal disturbances 2 .…”

Section: Introductionmentioning

confidence: 99%

Aetiological doctrines and prevalence of pellagra: 18th century to middle 20th century

Viljoen¹,

Bipath²,

Roos³

2018

S. Afr. J. Sci.

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Pellagra is characterised by dermatological, gastrointestinal and neuropsychiatric manifestations. Millions contracted the disease and hundreds of thousands died between the time it was first recorded until pellagra was finally recognised as a niacin-deficiency disease. Pellagra became epidemic when maize, with its limited bio-availability of nutrients such as niacin and tryptophan, became the staple food in the near-monophagic diets of the impoverished and institutionalised. By the mid-20th century, pellagra was all but eradicated in large parts. The decline in prevalence can largely be ascribed to a better understanding of the link between nutrition and disease, improvements in socio-economic conditions of workers and food enrichment. We briefly review aetiological doctrines on pellagra and the global spread of the disease from the early 18th century until the middle of the 20th century. In the final analysis, we examine the reasons for, and the legitimacy of, the persistent association between pellagra and the consumption of maize.

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Mechanisms of the Pellagragenic Effect of Leucine: Stimulation of Hepatic Tryptophan Oxidation by Administration of Branched-Chain Amino Acids to Healthy Human Volunteers and the Role of Plasma Free Tryptophan and Total Kynurenines

Cited by 26 publications

References 38 publications

Plasma amino acids and metabolic profiling of dairy cows in response to a bolus duodenal infusion of leucine

Plasma amino acids and metabolic profiling of dairy cows in response to a bolus duodenal infusion of leucine

Elevation of Kynurenine Metabolites in Rat Liver and Serum: A Potential Additional Mechanism of the Alcohol Aversive and Anti-cancer Effects of Disulfiram?

Aetiological doctrines and prevalence of pellagra: 18th century to middle 20th century

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