Métabolisme et fonction de l'histidine

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Histidine Metabolism and Function
Margaret E Brosnan, The Journal of Nutrition, Volume 150, Issue Supplement_1, October 2020, Pages 2570S–2575S,

Histidine is a dietary essential amino acid because it cannot be synthesized in humans. The WHO/FAO requirement for adults for histidine is 10 mg · kg body weight−1 · d−1. Histidine is required for synthesis of proteins. It plays particularly important roles in the active site of enzymes, such as serine proteases (e.g., trypsin) where it is a member of the catalytic triad. Excess histidine may be converted to trans-urocanate by histidine ammonia lyase (histidase) in liver and skin.

UV light in skin converts the trans form to cis-urocanate which plays an important protective role in skin. Liver is capable of complete catabolism of histidine by a pathway which requires folic acid for the last step, in which glutamate formiminotransferase converts the intermediate N-formiminoglutamate to glutamate, 5,10 methenyl-tetrahydrofolate, and ammonia. Inborn errors have been recognized in all of the catabolic enzymes of histidine.

Histidine is required as a precursor of carnosine in human muscle and parts of the brain where carnosine appears to play an important role as a buffer and antioxidant. It is synthesized in the tissue by carnosine synthase from histidine and β-alanine, at the expense of ATP hydrolysis. Histidine can be decarboxylated to histamine by histidine decarboxylase.

This reaction occurs in the enterochromaffin-like cells of the stomach, in the mast cells of the immune system, and in various regions of the brain where histamine may serve as a neurotransmitter.

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Histidine is one of the least abundant amino acids in whole body protein in humans. Tessari (6) calculated the total body protein content of various amino acids in humans. The most abundant were proline (1328 g) and glycine (1247 g), both important in structural proteins, whereas there were only 245 g histidine, second only to tryptophan at 88 g.

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It is now known that histidine is a nutritional requirement for adult humans as well, because they are unable to synthesize it

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Potential Benefits and Pitfalls of Histidine Supplementation for Cancer Therapy Enhancement
Boryana Petrova, The Journal of Nutrition, Volume 150, Issue Supplement_1, October 2020, Pages 2580S–2587S,

Dietary supplementation of the amino acid histidine has demonstrable benefits in various clinical conditions. Recent work in a pediatric leukemia mouse model exposed a surprising potential application of histidine supplementation for cancer therapy enhancement. These findings demand a deeper reassessment of the physiological effects and potential drawbacks of histidine supplementation. As pertinent to this question, we discuss the safety of high doses of histidine and its relevant metabolic fates in the human body. We refrain from recommendations or final conclusions because comprehensive preclinical evidence for safety and efficacy of histidine supplementation is still lacking. However, we emphasize the incentive to study the safety of histidine supplementation and its potential to improve the clinical outcome of pediatric blood cancers through a simple dietary supplementation. The need for comprehensive preclinical testing of histidine supplementation in healthy and tumor-bearing mice is fundamental, and we hope that this review will facilitate such studies.

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Carnosine supplementation studies (at 50–100 mg · kg−1 · d−1) have reported antineoplastic, cardiovascular-protective, antidiabetic, anti-ischemic, and neuroprotective effects (30), and carnosine is currently undergoing clinical trials for some conditions related to these effects (clinicaltrials.gov, 40 total, 14 currently ongoing as of May 6, 2020). It is currently unclear how these effects will confound and/or synergize with a potential positive benefit of histidine supplementation in antifolate cancer therapy.

Carnosine was shown to serve as a non–mast cell precursor for histidine, which is directed toward histamine synthesis after trauma or stress. As a proposed source for histamine, carnosine concentrations were observed to decrease in wounded muscle of cockerels or rats after femur fracture and the decrease was prevented by injections of histamine or histidine

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Benefits and Adverse Effects of Histidine Supplementation
Anna E Thalacker-Mercer, The Journal of Nutrition, Volume 150, Issue Supplement_1, October 2020, Pages 2588S–2592S,

Histidine is a nutritionally essential amino acid with many recognized benefits to human health, while circulating concentrations of histidine decline in pathologic conditions [e.g., chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)].

The purpose of this review is to examine the existing literature regarding the benefits of histidine intake, the adverse effects of excess histidine, and the upper tolerance level for histidine. Supplementation with doses of 4.0–4.5 g histidine/d and increased dietary histidine intake are associated with decreased BMI, adiposity, markers of glucose homeostasis (e.g., HOMA-IR, fasting blood glucose, 2-h postprandial blood glucose), proinflammatory cytokines, and oxidative stress. It is unclear from the limited number of studies in humans whether the improvements in glucoregulatory markers, inflammation, and oxidative stress are due to reduced BMI and adiposity, increased carnosine (a metabolic product of histidine with antioxidant effects), or both.

Histidine intake also improves cognitive function (e.g., reduces appetite, anxiety, and stress responses and improves sleep) potentially through the metabolism of histidinne to histamie; however, this relation is ambiguous in humans. At high intakes of histidine (>24 g/d), studies report adverse effects of histidine such as decreased serum zinc and cognitive impairment. There is limited research on the effects of histidine intake at doses between 4.5 and 24 g/d, and thus, a tolerable upper level has not been established. Determining tolerance to histidine supplementation has been limited by small sample sizes and, more important, a lack of a clear biomarker for histidine supplementation. The U-shaped curve of circulating zinc concentrations with histidine supplementation could be exploited as a relevant biomarker for supplemental histidine tolerance. Histidine is an important amino acid and may be necessary as a supplement in some populations; however, gaps in knowledge, which this review highlights, need to be addressed scientifically.

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Histidine supplementation over a long duration is not associated with carcinogenicity and may actually improve cancer therapies.

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Histidine supplementation has been shown to affect circulating zinc concentrations via altering absorption, urinary excretion, and/or metabolism of zinc. Histidine is a chelator of zinc, which may explain increased intestinal absorption of zinc during histidine supplementation in rats (34). In humans, at a dose of 4 g histidine/d for 2 wk, serum or urinary zinc concentrations were not altered (25). Unlike lower concentrations of supplemental histidine, at high concentrations of histidine (>24 g/d), urinary zinc concentrations increase in humans (33, 35) and in rats (36).

In humans, high doses of histidine have been used to induce zinc deficiency (35). Thus, there is perhaps a U-shaped curve for zinc metabolism in the context of histidine; however, to date, there is limited knowledge of the impact of histidine doses between 4 and 24 g/d on zinc absorption, metabolism, and urinary excretion. A recent study demonstrated that 4–12 g histidine/d does not affect serum or urine zinc concentrations; however, at 16 g histidine/d for 4 wk, there was a significant decrease in serum zinc likely due to an increase in urinary zinc excretion, although the increase in urinary zinc was only a trend

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Tolerance to graded dosages of histidine supplementation in healthy human adults
Mary E Gheller Am J Clin Nutr. 2020 Aug 7;

Background: Histidine is an essential amino acid with health benefits that may warrant histidine supplementation; however, the clinical safety of histidine intake above the average dietary intake (1.52-5.20 g/d) needs to be vetted.

Objectives: We aimed to determine the tolerance to graded dosages of histidine in a healthy adult population.

Methods: Healthy adults aged 21-50 y completed graded dosages of histidine supplement (4, 8, and 12 g/d, Study 1) (n = 20 men and n = 20 women) and/or a 16-g/d dosage of histidine (Study 2, n = 21 men and n = 19 women); 27 participants (n = 12 men and n = 15 women) completed both studies. After study enrollment and baseline measures, participants consumed encapsulated histidine for 4 wk followed by a 3-wk recovery period. Primary outcomes included vitals, select biochemical analytes, anthropometry, serum zinc, and body composition (via DXA).

Results: No changes in vitals or body composition occurred with histidine supplementation in either study. Plasma histidine (measured in subjects who completed all dosages for Studies 1 and 2) was elevated at the 12- and 16-g/d dosages (compared with 0-8 g/d, P < 0.05) and blood urea nitrogen increased with dosage (P = 0.013) and time (P < 0.001) in Study 1 and with time in Study 2 (P < 0.001). In Study 1, mean ferritin concentrations were lower in 12 g/d (46.0 ng/mL; 95% CI: 34.8, 60.9 ng/mL) than in 4 g/d (51.6 ng/mL; 95% CI: 39.0, 68.4 ng/mL; P = 0.038). In Study 2, 16 g/d increased mean aspartate aminotransferase from baseline (19 U/L; 95% CI: 17, 22 U/L) to week 4 (24 U/L; 95% CI: 21, 27 U/L; P < 0.001) and mean serum zinc decreased from baseline (0.75 μg/dL; 95% CI: 0.71, 0.80 μg/dL) to week 4 (0.70 μg/dL; 95% CI: 0.66, 0.74 μg/dL; P = 0.011).

Conclusions: Although values remained within the normal reference ranges for all analytes measured, in all dosages tested, the human no-observed adverse effect level was determined to be 8 g/d owing to changes in blood parameters at the 12-g/d dosage.

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Traduction de l'étude

tolérance à des doses graduées de supplémentation en histidine chez des adultes humains en bonne santé
Mary E Gheller Am J Clin Nutr. 7 août 2020;

Contexte: L'histidine est un acide aminé essentiel avec des avantages pour la santé qui peuvent justifier une supplémentation en histidine; cependant, l'innocuité clinique d'un apport d'histidine supérieur à l'apport alimentaire moyen (1,52 à 5,20 g / j) doit être vérifiée.

Objectifs: Nous visions à déterminer la tolérance à des doses graduées d'histidine dans une population adulte en bonne santé.

Méthodes: Des adultes en bonne santé âgés de 21 à 50 ans ont complété des doses graduées de supplément d'histidine (4, 8 et 12 g / j, étude 1) (n = 20 hommes et n = 20 femmes) et / ou une dose de 16 g / j d'histidine (étude 2, n = 21 hommes et n = 19 femmes); 27 participants (n = 12 hommes et n = 15 femmes) ont terminé les deux études. Après l'inscription à l'étude et les mesures de base, les participants ont consommé de l'histidine encapsulée pendant 4 semaines, suivies d'une période de récupération de 3 semaines. Les principaux critères de jugement comprenaient les signes vitaux, certains analytes biochimiques, l'anthropométrie, le zinc sérique et la composition corporelle (via DXA).

Résultats: Aucune modification des signes vitaux ou de la composition corporelle n'a été observée avec la supplémentation en histidine dans les deux études. L'histidine plasmatique (mesurée chez les sujets ayant terminé toutes les doses pour les études 1 et 2) était élevée aux doses de 12 et 16 g / j (par rapport à 0-8 g / j, P <0,05) et l'azote uréique sanguin augmenté avec la dose (P = 0,013) et le temps (P <0,001) dans l'étude 1 et avec le temps dans l'étude 2 (P <0,001). Dans l'étude 1, les concentrations moyennes de ferritine étaient plus faibles dans 12 g / j (46,0 ng / mL; IC à 95%: 34,8, 60,9 ng / mL) que dans 4 g / j (51,6 ng / mL; IC à 95%: 39,0, 68,4 ng / mL; P = 0,038). Dans l'étude 2, 16 g / j ont augmenté la moyenne d'aspartate aminotransférase entre le départ (19 U / L; IC à 95%: 17, 22 U / L) et la semaine 4 (24 U / L; IC à 95%: 21, 27 U / L) ; P <0,001) et le zinc sérique moyen ont diminué par rapport au départ (0,75 μg / dL; IC à 95%: 0,71, 0,80 μg / dL) à la semaine 4 (0,70 μg / dL; IC à 95%: 0,66, 0,74 μg / dL; P = 0,011).

Conclusions: Bien que les valeurs soient restées dans les plages de référence normales pour tous les analytes mesurés, pour toutes les doses testées, le niveau d'effet indésirable humain sans effet indésirable observé a été déterminé à 8 g / j en raison des modifications des paramètres sanguins à la dose de 12 g / j .