L-histidine (HIS) is an essential amino acid with unique roles in proton buffering, metal ion chelation, scavenging of reactive oxygen and nitrogen species, erythropoiesis, and the histaminergic system. Several HIS-rich proteins (e.g., haemoproteins, HIS-rich glycoproteins, histatins, HIS-rich calcium-binding protein, and filaggrin), HIS-containing dipeptides (particularly carnosine), and methyl- and sulphur-containing derivatives of HIS (3-methylhistidine, 1-methylhistidine, and ergothioneine) have specific functions. The unique chemical properties and physiological functions are the basis of the theoretical rationale to suggest HIS supplementation in a wide range of conditions. Several decades of experience have confirmed the effectiveness of HIS as a component of solutions used for organ preservation and myocardial protection in cardiac surgery. Further studies are needed to elucidate the effects of HIS supplementation on neurological disorders, atopic dermatitis, metabolic syndrome, diabetes, uraemic anaemia, ulcers, inflammatory bowel diseases, malignancies, and muscle performance during strenuous exercise. Signs of toxicity, mutagenic activity, and allergic reactions or peptic ulcers have not been reported, although HIS is a histamine precursor. Of concern should be findings of hepatic enlargement and increases in ammonia and glutamine and of decrease in branched-chain amino acids (valine, leucine, and isoleucine) in blood plasma indicating that HIS supplementation is inappropriate in patients with liver disease.

Department of Physiology Faculty of Medicine in Hradec Králové Charles University Šimkova 870 500 38 Hradec Kralove Czech Republic

Zobrazit více v PubMed

Pinals R.S., Harris E.D., Burnett J.B., Gerber D.A. Treatment of rheumatoid arthritis with L-histidine: A randomized, placebo-controlled, double-blind trial. J. Rheumatol. 1977;4:414–419. PubMed

Giordano C., De Santo N.G., Rinaldi S., Acone D., Esposito R., Gallo B. Histidine for treatment of uraemic anaemia. Br. Med. J. 1973;4:714–716. doi: 10.1136/bmj.4.5894.714. PubMed DOI PMC

Tan S.P., Brown S.B., Griffiths C.E., Weller R.B., Gibbs N.K. Feeding filaggrin: Effects of l-histidine supplementation in atopic dermatitis. Clin. Cosmet. Investig. Dermatol. 2017;10:403–411. doi: 10.2147/CCID.S146760. PubMed DOI PMC

DiNicolantonio J.J., McCarty M.F., OKeefe J.H. Role of dietary histidine in the prevention of obesity and metabolic syndrome. Open Heart. 2018;5:e000676. doi: 10.1136/openhrt-2017-000676. PubMed DOI PMC

Matsukura T., Tanaka H. Applicability of zinc complex of L-carnosine for medical use. Biochemistry (Mosc.) 2000;65:817–823. PubMed

Babizhayev M.A., Guiotto A., Kasus-Jacobi A. N-Acetylcarnosine and histidyl-hydrazide are potent agents for multitargeted ophthalmic therapy of senile cataracts and diabetic ocular complications. J. Drug. Target. 2009;17:36–63. doi: 10.1080/10611860802438736. PubMed DOI

Hisatsune T., Kaneko J., Kurashige H., Cao Y., Satsu H., Totsuka M., Katakura Y., Imabayashi E., Matsuda H. Effect of anserine/carnosine supplementation on verbal episodic memory in elderly people. J. Alzheimers Dis. 2016;50:149–159. doi: 10.3233/JAD-150767. PubMed DOI PMC

Boldyrev A., Fedorova T., Stepanova M., Dobrotvorskaya I., Kozlova E., Boldanova N., Bagyeva G., Ivanova-Smolenskaya I., Illarioshkin S. Carnosine [corrected] increases efficiency of DOPA therapy of Parkinson’s disease: A pilot study. Rejuvenation Res. 2008;11:821–827. doi: 10.1089/rej.2008.0716. PubMed DOI

Suzuki Y., Nakao T., Maemura H., Sato M., Kamahara K., Morimatsu F., Takamatsu K. Carnosine and anserine ingestion enhances contribution of nonbicarbonate buffering. Med. Sci. Sports Exerc. 2006;38:334–338. PubMed

Derave W., Everaert I., Beeckman S., Baguet A. Muscle carnosine metabolism and beta-alanine supplementation in relation to exercise and training. Sports Med. 2010;40:247–263. doi: 10.2165/11530310-000000000-00000. PubMed DOI

Abe H. Role of histidine-related compounds as intracellular proton buffering constituents in vertebrate muscle. Biochemistry (Mosc.) 2000;65:757–765. PubMed

Edelman J.J., Seco M., Dunne B., Matzelle S.J., Murphy M., Joshi P., Yan T.D., Wilson M.K., Bannon P.G., Vallely M.P., et al. Custodiol for myocardial protection and preservation: A systematic review. Ann. Cardiothorac. Surg. 2013;2:717–728. PubMed PMC

Kahn J., Schemmer P. Comprehensive review on Custodiol-N (HTK-N) and its molecular side of action for organ preservation. Curr. Pharm. Biotechnol. 2017;18:1237–1248. doi: 10.2174/1389201019666180409165154. PubMed DOI

Rao F., Yang J., Gong C., Huang R., Wang Q., Shen J. Systematic review of preservation solutions for allografts for liver transplantation based on a network meta-analysis. Pt AInt. J. Surg. 2018;54:1–6. doi: 10.1016/j.ijsu.2018.04.024. PubMed DOI

Poon I.K., Patel K.K., Davis D.S., Parish C.R., Hulett M.D. Histidine-rich glycoprotein: The Swiss Army knife of mammalian plasma. Blood. 2011;117:2093–2101. doi: 10.1182/blood-2010-09-303842. PubMed DOI

Boldyrev A.A., Aldini G., Wim D. Physiology and pathophysiology of carnosine. Physiol. Rev. 2013;93:1803–1845. doi: 10.1152/physrev.00039.2012. PubMed DOI

Smolik S., Nogaj P., Szpakowska A., Lodowska J., Weglarz L. The role of amino acids supplementation of protective Na2H2EDTA containing ointments in chelation of allergenic metal ions. Acta Pol. Pharm. 2010;67:737–740. PubMed

Trombley P.Q., Horning M.S., Blakemore L.J. Interactions between carnosine and zinc and copper: Implications for neuromodulation and neuroprotection. Biochemistry (Mosc.) 2000;65:807–816. PubMed

Dahl T.A., Midden W.R., Hartman P.E. Some prevalent biomolecules as defenses against singlet oxygen damage. Photochem. Photobiol. 1988;47:357–362. doi: 10.1111/j.1751-1097.1988.tb02737.x. PubMed DOI

Hartman P.E., Hartman Z., Ault K.T. Scavenging of singlet molecular oxygen by imidazole compounds: High and sustained activities of carboxy terminal histidine dipeptides and exceptional activity of imidazole-4-acetic acid. Photochem. Photobiol. 1990;51:59–66. doi: 10.1111/j.1751-1097.1990.tb01684.x. PubMed DOI

Chan W.K., Decker E.A., Chow C.K., Boissonneault G.A. Effect of dietary carnosine on plasma and tissue antioxidant concentrations and on lipid oxidation in rat skeletal muscle. Lipids. 1994;29:461–466. doi: 10.1007/BF02578242. PubMed DOI

Hipkiss A.R. On the enigma of carnosine’s anti-ageing actions. Exp. Gerontol. 2009;44:237–242. doi: 10.1016/j.exger.2008.11.001. PubMed DOI

Menini S., Iacobini C., Fantauzzi C.B., Pugliese G. L-carnosine and its derivatives as new therapeutic agents for the prevention and treatment of vascular complications of diabetes. Curr. Med. Chem. 2019 doi: 10.2174/0929867326666190711102718. PubMed DOI

Song B.C., Joo N.-S., Aldini G., Yeum K.-J. Biological functions of histidine-dipeptides and metabolic syndrome. Nutr. Res. Pract. 2014;8:3–10. doi: 10.4162/nrp.2014.8.1.3. PubMed DOI PMC

Ihara H., Kakihana Y., Yamakage A., Kai K., Shibata T., Nishida M., Yamda K.-I., Uchida K. 2-Oxo-histidine-containing dipeptides are functional oxidation products. J. Biol. Chem. 2019;294:1279–1289. doi: 10.1074/jbc.RA118.006111. PubMed DOI PMC

Rose W.C., Haines W.J., Warner D.T., Johnson J.E. The amino acid requirements of man. II. The role of threonine and histidine. J. Biol. Chem. 1951;188:49–58. PubMed

Kopple J.D., Swendseid M.E. Evidence that histidine is an essential amino acid in normal and chronically uremic man. J. Clin. Investig. 1975;55:881–891. doi: 10.1172/JCI108016. PubMed DOI PMC

Kopple J.D., Swendseid M.E. Effect of histidine intake of plasma and urine histidine levels, nitrogen balance and N tau-methylhistidine excretion in normal and chronically uremic men. J. Nutr. 1981;111:931–942. doi: 10.1093/jn/111.6.931. PubMed DOI

Clemens R.A., Kopple J.D., Swendseid M.E. Metabolic effects of histidine-deficient diets fed to growing rats by gastric tube. J. Nutr. 1984;114:2138–2146. doi: 10.1093/jn/114.11.2138. PubMed DOI

Anderson H.L., Soon Cho E., Krause P.A., Hanson K.C., Krause G.F., Wixom R.L. Effects of dietary histidine and arginine on nitrogen retention of men. J. Nutr. 1977;107:2067–2077. doi: 10.1093/jn/107.11.2067. PubMed DOI

Cho E.S., Anderson H.L., Wixom R.L., Hanson K.C., Krause G.F. Long-term effects of low histidine intake on men. J. Nutr. 1984;114:369–384. doi: 10.1093/jn/114.2.369. PubMed DOI

Nasset E.S., Gatewood V.H. Nitrogen balance and hemoglobin of adult rats fed amino acid diets low in L- and D-histidine. J. Nutr. 1954;53:163–176. doi: 10.1093/jn/53.2.163. PubMed DOI

Gilbert J.A., Bendsen N.T., Tremblay A., Astrup A. Effect of proteins from different sources on body composition. Nutr. Metab. Cardiovasc. Dis. 2011;21:B16–B31. doi: 10.1016/j.numecd.2010.12.008. PubMed DOI

Sasahara I., Fujimura N., Nozawa Y., Furuhata Y., Sato H. The effect of histidine on mental fatigue and cognitive performance in subjects with high fatigue and sleep disruption scores. Physiol. Behav. 2015;147:238–244. doi: 10.1016/j.physbeh.2015.04.042. PubMed DOI

Currell K., Derave W., Everaert I., McNaughton L., Slater G., Burke L.M., Stear S.J., Castell L.M. A-Z of nutritional supplements: Dietary supplements, sports nutrition foods and ergogenic aids for health and performance-Part 20. Br. J. Sports Med. 2011;45:530–532. doi: 10.1136/bjsports-2011-090020. PubMed DOI

Nozawa Y., Ishizaki T., Kuroda M., Noguchi T. Effect of dried-bonito broth intake on peripheral blood flow, mood, and oxidative stress marker in humans. Physiol. Behav. 2008;93:267–273. doi: 10.1016/j.physbeh.2007.08.021. PubMed DOI

Kuroda M., Ishizaki T., Maruyama T., Takatsuka Y., Kuboki T. Effect of dried-bonito broth on mental fatigue and mental task performance in subjects with a high fatigue score. Physiol. Behav. 2007;92:957–962. doi: 10.1016/j.physbeh.2007.07.002. PubMed DOI

Baslow M.H., Guilfoyle D.N. N-acetyl-L-histidine, a prominent biomolecule in brain and eye of poikilothermic vertebrates. Biomolecules. 2015;5:635–646. doi: 10.3390/biom5020635. PubMed DOI PMC

Holeček M., Vodeničarovová M. Effects of histidine load on ammonia, amino acid, and adenine nucleotide concentrations in rats. Amino Acids. 2019;51:1667–1680. PubMed

Steinert P.M., Cantieri J.S., Teller D.C., Lonsdale-Eccles J.D., Dale B.A. Characterization of a class of cationic proteins that specifically interact with intermediate filaments. Proc. Natl. Acad. Sci. USA. 1981;78:4097–4101. doi: 10.1073/pnas.78.7.4097. PubMed DOI PMC

Hug D.H., Hunter J.K., Dunkerson D.D. The potential role for urocanic acid and sunlight in the immune suppression associated with protein malnutrition. J. Photochem. Photobiol. B. 1998;44:117–123. doi: 10.1016/S1011-1344(98)00130-4. PubMed DOI

Kang-Lee Y.A., Harper A.E. Effect of induction of histidase on histidine metabolism in vivo. J. Nutr. 1979;109:291–299. doi: 10.1093/jn/109.2.291. PubMed DOI

Torres N., Martínez L., Alemán G., Bourges H., Tovar A.R. Histidase expression is regulated by dietary protein at the pretranslational level in rat liver. J. Nutr. 1998;128:818–824. doi: 10.1093/jn/128.5.818. PubMed DOI

Luhby A.L., Cooperman J.M., Teller D.N. Urinary excretion of formiminoglutamic acid: Application in diagnosis of clinical folic acid deficiency. Am. J. Clin. Nutr. 1959;7:397–406. doi: 10.1093/ajcn/7.4.397. PubMed DOI

Silverman M., Gardine R.C., Condit P.T. A method for the detection of N-formiminoglutamic acid in urine. J. Natl. Cancer Inst. 1958;20:71–77. PubMed

Meléndez-Hevia E., De Paz-Lugo P., Cornish-Bowden A., Cárdenas M.L. A weak link in metabolism: The metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis. J. Biosci. 2009;34:853–872. PubMed

Fell D., Steele R.D. Effect of methionine on in vivo histidine metabolism in rats. J. Nutr. 1983;113:860–866. doi: 10.1093/jn/113.4.860. PubMed DOI

Billings R.E., Noker P.E., Tephly T.R. The role of methionine in regulating folate-dependent reactions in isolated rat hepatocytes. Arch. Biochem. Biophys. 1981;208:108–120. doi: 10.1016/0003-9861(81)90129-6. PubMed DOI

Cynober L. Metabolism of dietary glutamate in adults. Ann. Nutr. Metab. 2018;73:5–14. doi: 10.1159/000494776. PubMed DOI

Noguchi T., Minatogawa Y., Okuno E., Kido R. Organ distribution of rat histidine-pyruvate aminotransferase isoenzymes. Biochem. J. 1976;157:635–641. doi: 10.1042/bj1570635. PubMed DOI PMC

Romero S.A., Minson C.T., Halliwill J.R. The cardiovascular system after exercise. J. Appl. Physiol. (1985). 2017;122:925–932. doi: 10.1152/japplphysiol.00802.2016. PubMed DOI PMC

Schayer R.W. Histamine and autonomous responses of the microcirculation; relationship to glucocorticoid action. Ann. N. Y. Acad. Sci. 1964;116:891–898. doi: 10.1111/j.1749-6632.1964.tb52555.x. PubMed DOI

Ayada K., Tsuchiya M., Yoneda H., Yamaguchi K., Kumamoto H., Sasaki S., Tadano T., Watanabe M., Endo Y. Induction of the histamine-forming enzyme histidine decarboxylase in skeletal muscles by prolonged muscular work: Histological demonstration and mediation by cytokines. Biol. Pharm. Bull. 2017;40:1326–1330. doi: 10.1248/bpb.b17-00112. PubMed DOI

Savany A., Cronenberger L. Properties of histidine decarboxylase from rat gastric mucosa. Eur. J. Biochem. 1982;123:593–599. doi: 10.1111/j.1432-1033.1982.tb06574.x. PubMed DOI

Jeong H.J., Moon P.D., Kim S.J., Seo J.U., Kang T.H., Kim I.J., Kang I.C., Um J.Y., Kim H.M., Hong S.H. Activation of hypoxia-inducible factor-1 regulates human histidine decarboxylase expression. Cell. Mol. Life. Sci. 2009;66:1309–1319. doi: 10.1007/s00018-009-9001-1. PubMed DOI PMC

Nizamutdinova I.T., Maejima D., Nagai T., Meininger C.J., Gashev A.A. Histamine as an endothelium-derived relaxing factor in aged mesenteric lymphatic vessels. Lymphat. Res. Biol. 2017;15:136–145. doi: 10.1089/lrb.2016.0062. PubMed DOI PMC

Thangam E.B., Jemima E.A., Singh H., Baig M.S., Khan M., Mathias C.B., Church M.K., Saluja R. The role of histamine and histamine receptors in mast cell-mediated allergy and inflammation: The hunt for new therapeutic targets. Front. Immunol. 2018;9:1873. doi: 10.3389/fimmu.2018.01873. PubMed DOI PMC

Lee N.S., Fitzpatrick D., Meier E., Fisher H. Influence of dietary histidine on tissue histamine concentration, histidine decarboxylase and histamine methyltransferase activity in the rat. Agents Actions. 1981;11:307–311. doi: 10.1007/BF01982463. PubMed DOI

Martin S.K., Harmon D.L., Conway C.E., Vanzant E.S., McLeod K.R. Influence of dietary histidine on basophil release, circulating concentration, and urinary excretion of histamine in domestic felines. J. Appl. Res. Vet. Med. 2012;10:289–299.

Lozeva V., Tarhanen J., Attila M., Männistö P.T., Tuomisto L. Brain histamine and histamine H3 receptors following repeated L-histidine administration in rats. Life Sci. 2003;73:1491–1503. doi: 10.1016/S0024-3205(03)00478-8. PubMed DOI

Yoshikawa T., Nakamura T., Shibakusa T., Sugita M., Naganuma F., Iida T., Miura Y., Mohsen A., Harada R., Yanai K. Insufficient intake of L-histidine reduces brain histamine and causes anxiety-like behaviors in male mice. J. Nutr. 2014;144:1637–1641. doi: 10.3945/jn.114.196105. PubMed DOI

Kasaoka S., Tsuboyama-Kasaoka N., Kawahara Y., Inoue S., Tsuji M., Ezaki O., Kato H., Tsuchiya T., Okuda H., Nakajima S. Histidine supplementation suppresses food intake and fat accumulation in rats. Nutrition. 2004;20:991–996. doi: 10.1016/j.nut.2004.08.006. PubMed DOI

Goto K., Kasaoka S., Takizawa M., Ogawa M., Tsuchiya T., Nakajima S. Bitter taste and blood glucose are not involved in the suppressive effect of dietary histidine on food intake. Neurosci. Lett. 2007;420:106–109. doi: 10.1016/j.neulet.2007.03.074. PubMed DOI

Asahi R., Tanaka K., Fujimi T.J., Kanzawa N., Nakajima S. Proline decreases the suppressive effect of histidine on food intake and fat accumulation. J. Nutr. Sci. Vitaminol. (Tokyo) 2016;62:277–280. doi: 10.3177/jnsv.62.277. PubMed DOI

Okusha Y., Hirai Y., Maezawa H., Hisadome K., Inoue N., Yamazaki Y., Funahashi M. Effects of intraperitoneally administered L-histidine on food intake, taste, and visceral sensation in rats. J. Physiol. Sci. 2017;67:467–474. doi: 10.1007/s12576-016-0476-x. PubMed DOI PMC

Sheiner J.B., Morris P., Anderson G.H. Food intake suppression by histidine. Pharmacol. Biochem. Behav. 1985;23:721–726. doi: 10.1016/0091-3057(85)90061-9. PubMed DOI

Vaziri P., Dang K., Anderson G.H. Evidence for histamine involvement in the effect of histidine loads on food and water intake in rats. J. Nutr. 1997;127:1519–1526. doi: 10.1093/jn/127.8.1519. PubMed DOI

Yoshimatsu H., Chiba S., Tajima D., Akehi Y., Sakata T. Histidine suppresses food intake through its conversion into neuronal histamine. Exp. Biol. Med. (Maywood) 2002;227:63–68. doi: 10.1177/153537020222700111. PubMed DOI

Nagasawa T., Yoshizawa F., Nishizawa N. Plasma N tau-methylhistidine concentration is a sensitive index of myofibrillar protein degradation during starvation in rats. Biosci. Biotechnol. Biochem. 1996;60:501–502. doi: 10.1271/bbb.60.501. PubMed DOI

Myint T., Fraser G.E., Lindsted K.D., Knutsen S.F., Hubbard R.W., Bennett H.W. Urinary 1-methylhistidine is a marker of meat consumption in Black and in White California Seventh-day Adventists. Am. J. Epidemiol. 2000;152:752–755. doi: 10.1093/aje/152.8.752. PubMed DOI

Cheah I.K., Halliwell B. Ergothioneine; antioxidant potential, physiological function and role in disease. Biochim. Biophys. Acta. 2012;1822:784–793. doi: 10.1016/j.bbadis.2011.09.017. PubMed DOI

Sotgia S., Zinellu A., Mangoni A.A., Pintus G., Attia J., Carru C., McEvoy M. Clinical and biochemical correlates of serum L-ergothioneine concentrations in community-dwelling middle-aged and older adults. PLoS ONE. 2014;9:e84918. doi: 10.1371/journal.pone.0084918. PubMed DOI PMC

Hatano T., Saiki S., Okuzumi A., Mohney R.P., Hattori N. Identification of novel biomarkers for Parkinson’s disease by metabolomic technologies. J. Neurol. Neurosurg. Psychiatry. 2016;87:295–301. doi: 10.1136/jnnp-2014-309676. PubMed DOI

Forster R., Spézia F., Papineau D., Sabadie C., Erdelmeier I., Moutet M., Yadan J.C. Reproductive safety evaluation of L-Ergothioneine. Food Chem. Toxicol. 2015;80:85–91. doi: 10.1016/j.fct.2015.02.019. PubMed DOI

Halliwell B., Cheah I.K., Tang R.M.Y. Ergothioneine—a diet—derived antioxidant with therapeutic potential. FEBS Lett. 2018;592:3357–3366. doi: 10.1002/1873-3468.13123. PubMed DOI

Berenbrink M. Evolution of vertebrate haemoglobins: Histidine side chains, specific buffer value and Bohr effect. Respir. Physiol. Neurobiol. 2006;154:165–184. doi: 10.1016/j.resp.2006.01.002. PubMed DOI

Melino S., Santone C., Di Nardo P., Sarkar B. Histatins: Salivary peptides with copper(II)- and zinc(II)-binding motifs: Perspectives for biomedical applications. FEBS J. 2014;281:657–672. doi: 10.1111/febs.12612. PubMed DOI

Arvanitis D.A., Vafiadaki E., Johnson D.M., Kranias E.G., Sanoudou D. The histidine-rich calcium binding protein in regulation of cardiac rhythmicity. Front. Physiol. 2018;9:1379. doi: 10.3389/fphys.2018.01379. PubMed DOI PMC

González-Estrada M.T., Freeman W.J. Effects of carnosine on olfactory bulb EEG, evoked potentials and DC potentials. Brain Res. 1980;202:373–386. PubMed

Hill C.A., Harris R.C., Kim H.J., Harris B.D., Sale C., Boobis L.H., Kim C.K., Wise J.A. Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity. Amino Acids. 2007;32:225–233. doi: 10.1007/s00726-006-0364-4. PubMed DOI

Harris R.C., Wise J.A., Price K.A., Kim H.J., Kim C.K., Sale C. Determinants of muscle carnosine content. Amino Acids. 2012;43:5–12. doi: 10.1007/s00726-012-1233-y. PubMed DOI PMC

Teufel M., Saudek V., Ledig J.-P., Bernhardt A., Boularand S., Carreau A., Cairns N.J., Carter C., Cowley D.J., Duverger D., et al. Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase. J. Biol. Chem. 2003;278:6521–6531. doi: 10.1074/jbc.M209764200. PubMed DOI

Bauer K. Carnosine and homocarnosine, the forgotten, enigmatic peptides of the brain. Neurochem. Res. 2005;30:1339–1345. doi: 10.1007/s11064-005-8806-z. PubMed DOI

Park Y.J., Volpe S.L., Decker E.A. Quantitation of carnosine in humans plasma after dietary consumption of beef. J. Agric. Food. Chem. 2005;53:4736–4739. doi: 10.1021/jf047934h. PubMed DOI

Jackson M.C., Scollard D.M., Mack R.J., Lenney J.F. Localization of a novel pathway for the liberation of GABA in the human CNS. Brain Res. Bull. 1994;33:379–385. doi: 10.1016/0361-9230(94)90280-1. PubMed DOI

Drapała A., Bielińska K., Konopelski P., Pączek L., Ufnal M. His-Leu, an angiotensin I-derived peptide, does not affect haemodynamics in rats. J. Renin Angiotensin Aldosterone Syst. 2018;19:1470320318808879. PubMed PMC

Feng R.N., Niu Y.C., Sun X.W., Li Q., Zhao C., Wang C., Guo F.C., Sun C.H., Li Y. Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: A randomised controlled trial. Diabetologia. 2013;56:985–994. doi: 10.1007/s00125-013-2839-7. PubMed DOI

del Favero S., Roschel H., Solis M.Y., Hayashi A.P., Artioli G.G., Otaduy M.C., Benatti F.B., Harris R.C., Wise J.A., Leite C.C., et al. Beta-alanine (Carnosyn™) supplementation in elderly subjects (60–80 years): Effects on muscle carnosine content and physical capacity. Amino Acids. 2012;43:49–56. doi: 10.1007/s00726-011-1190-x. PubMed DOI PMC

Blancquaert L., Everaert I., Missinne M., Baguet A., Stegen S., Volkaert A., Petrovic M., Vervaet C., Achten E., DE Maeyer M., et al. Effects of histidine and β-alanine supplementation on human muscle carnosine storage. Med. Sci. Sports Exerc. 2017;49:602–609. doi: 10.1249/MSS.0000000000001213. PubMed DOI

Varanoske A.N., Hoffman J.R., Church D.D., Coker N.A., Baker K.M., Dodd S.J., Oliveira L.P., Dawson V.L., Wang R., Fukuda D.H., et al. β-Alanine supplementation elevates intramuscular carnosine content and attenuates fatigue in men and women similarly but does not change muscle l-histidine content. Nutr. Res. 2017;48:16–25. doi: 10.1016/j.nutres.2017.10.002. PubMed DOI

Harris R.C., Tallon M.J., Dunnett M., Boobis L., Coakley J., Kim H.J., Fallowfield J.L., Hill C.A., Sale C., Wise J.A. The absorption of orally supplied beta-alanine and its effect on muscle carnosine synthesis in human vastus lateralis. Amino Acids. 2006;30:279–289. doi: 10.1007/s00726-006-0299-9. PubMed DOI

Furst T., Massaro A., Miller C., Williams B.T., LaMacchia Z.M., Horvath P.J. β-Alanine supplementation increased physical performance and improved executive function following endurance exercise in middle aged individuals. J. Int. Soc. Sports. Nutr. 2018;15:32. doi: 10.1186/s12970-018-0238-7. PubMed DOI PMC

Jones R.L., Barnett C.T., Davidson J., Maritza B., Fraser W.D., Harris R., Sale C. β-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed. Eur. J. Appl. Physiol. 2017;117:867–879. doi: 10.1007/s00421-017-3569-1. PubMed DOI PMC

de Andrade Kratz C., de Salles Painelli V., de Andrade Nemezio K.M., da Silva R.P., Franchini E., Zagatto A.M., Gualano B., Artioli G.G. Beta-alanine supplementation enhances judo-related performance in highly-trained athletes. J. Sci. Med. Sport. 2017;20:403–408. doi: 10.1016/j.jsams.2016.08.014. PubMed DOI

Saunders B., Elliott-Sale K., Artioli G.G., Swinton P.A., Dolan E., Roschel H., Sale C., Gualano B. β-alanine supplementation to improve exercise capacity and performance: A systematic review and meta-analysis. Br. J. Sports Med. 2017;51:658–669. doi: 10.1136/bjsports-2016-096396. PubMed DOI

Berti Zanella P., Donner Alves F., Guerini de Souza C. Effects of beta-alanine supplementation on performance and muscle fatigue in athletes and non-athletes of different sports: A systematic review. J. Sports Med. Phys. Fitness. 2017;57:1132–1141. PubMed

Lim J.K., Narang P.K., Overman D.O., Jacknowitz A.I. Beneficial effects of methionine and histidine in aspirin solutions on gastric mucosal damage in rats. J. Pharm. Sci. 1979;68:295–298. doi: 10.1002/jps.2600680310. PubMed DOI

Adachi N., Liu K., Arai T. Prevention of brain infarction by postischemic administration of histidine in rats. Brain Res. 2005;1039:220–223. doi: 10.1016/j.brainres.2005.01.061. PubMed DOI

Moradi-Arzeloo M., Farshid A.A., Tamaddonfard E., Asri-Rezaei S. Effects of histidine and vitamin C on isoproterenol-induced acute myocardial infarction in rats. Vet. Res. Forum. 2016;7:47–54. PubMed PMC

Farshid A.A., Tamaddonfard E., Simaee N., Mansouri S., Najafi S., Asri-Rezaee S., Alavi H. Effects of histidine and N-acetylcysteine on doxorubicin-induced cardiomyopathy in rats. Cardiovasc. Toxicol. 2014;14:153–161. doi: 10.1007/s12012-013-9239-6. PubMed DOI

Herculano B., Tamura M., Ohba A., Shimatani M., Kutsuna N., Hisatsune T. β-Alanyl-L-histidine rescues cognitive deficits caused by feeding a high fat diet in a transgenic mouse model of Alzheimer’s disease. J. Alzheimers Dis. 2013;33:983–997. doi: 10.3233/JAD-2012-121324. PubMed DOI

Rybakova Y.S., Boldyrev A.A. Effect of carnosine and related compounds on proliferation of cultured rat pheochromocytoma PC-12 cells. Bull. Exp. Biol. Med. 2012;154:136–140. doi: 10.1007/s10517-012-1894-2. PubMed DOI

Rybakova Y.S., Kalen A.L., Eckers J.C., Fedorova T.N., Goswami P.C., Sarsour E.H. Increased manganese superoxide dismutase and cyclin B1 expression in carnosine-induced inhibition of glioblastoma cell proliferation. Biomed. Khim. 2015;61:510–518. doi: 10.18097/PBMC20156104510. PubMed DOI

Mikuła-Pietrasik J., Książek K. L-Carnosine prevents the pro-cancerogenic activity of senescent peritoneal mesothelium towards ovarian cancer cells. Anticancer Res. 2016;36:665–671. PubMed

Iovine B., Oliviero G., Garofalo M., Orefice M., Nocella F., Borbone N., Piccialli V., Centore R., Mazzone M., Piccialli G., et al. The anti-proliferative effect of L-carnosine correlates with a decreased expression of hypoxia inducible factor 1 alpha in human colon cancer cells. PLoS ONE. 2014;9:e96755. doi: 10.1371/journal.pone.0096755. PubMed DOI PMC

Yan H., Guo Y., Zhang J., Ding Z., Ha W., Harding J.J. Effect of carnosine, aminoguanidine, and aspirin drops on the prevention of cataracts in diabetic rats. Mol. Vis. 2008;14:2282–2291. PubMed PMC

Cornelli U. Treatment of Alzheimer’s disease with a cholinesterase inhibitor combined with antioxidants. Neurodegener. Dis. 2010;7:193–202. doi: 10.1159/000295663. PubMed DOI

Baraniuk J.N., El-Amin S., Corey R., Rayhan R., Timbol C. Carnosine treatment for gulf war illness: A randomized controlled trial. Glob. J. Health Sci. 2013;5:69–81. doi: 10.5539/gjhs.v5n3p69. PubMed DOI PMC

Chengappa K.N., Turkin S.R., DeSanti S., Bowie C.R., Brar J.S., Schlicht P.J., Murphy S.L., Hetrick M.L., Bilder R., Fleet D. A preliminary, randomized, double-blind, placebo-controlled trial of L-carnosine to improve cognition in schizophrenia. Schizophr. Res. 2012;142:145–152. doi: 10.1016/j.schres.2012.10.001. PubMed DOI

Szcześniak D., Budzeń S., Kopeć W., Rymaszewska J. Anserine and carnosine supplementation in the elderly: Effects on cognitive functioning and physical capacity. Arch. Gerontol. Geriatr. 2014;59:485–490. PubMed

Lombardi C., Carubelli V., Lazzarini V., Vizzardi E., Bordonali T., Ciccarese C., Castrini A.I., Dei Cas A., Nodari S., Metra M. Effects of oral administration of orodispersible levo-carnosine on quality of life and exercise performance in patients with chronic heart failure. Nutrition. 2015;31:72–78. doi: 10.1016/j.nut.2014.04.021. PubMed DOI

Huang P.L. A comprehensive definition for metabolic syndrome. Dis. Model Mech. 2009;2:231–237. doi: 10.1242/dmm.001180. PubMed DOI PMC

Sun X., Feng R., Li Y., Lin S., Zhang W., Li Y., Sun C., Li S. Histidine supplementation alleviates inflammation in the adipose tissue of high-fat diet-induced obese rats via the NF-κB- and PPARγ-involved pathways. Br. J. Nutr. 2014;112:477–485. doi: 10.1017/S0007114514001056. PubMed DOI

Aldini G., Orioli M., Rossoni G., Savi F., Braidotti P., Vistoli G., Yeum K.J., Negrisoli G., Carini M. The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. J. Cell. Mol. Med. 2011;15:1339–1354. doi: 10.1111/j.1582-4934.2010.01101.x. PubMed DOI PMC

Lee Y.T., Hsu C.C., Lin M.H., Liu K.S., Yin M.C. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur. J. Pharmacol. 2005;513:145–150. doi: 10.1016/j.ejphar.2005.02.010. PubMed DOI

Brown B.E., Kim C.H., Torpy F.R., Bursill C.A., McRobb L.S., Heather A.K., Davies M.J., van Reyk D.M. Supplementation with carnosine decreases plasma triglycerides and modulates atherosclerotic plaque composition in diabetic apo E(-/-) mice. Atherosclerosis. 2014;232:403–409. doi: 10.1016/j.atherosclerosis.2013.11.068. PubMed DOI

Liu Y., Cotillard A., Vatier C., Bastard J.-P., Fellahi S., Stévant M., Allatif O., Langlois C., Bieuvelet S., Brochot A., et al. A dietary supplement containing cinnamon, chromium and carnosine decreases fasting plasma glucose and increases lean mass in overweight or obese pre-diabetic subjects: A randomized, placebo-controlled trial. PLoS ONE. 2015;10:e0138646. doi: 10.1371/journal.pone.0145315. PubMed DOI PMC

Niu Y.-C., Feng R.-N., Hou Y., Li K., Kang Z., Wang J., Sun C.-H., Li Y. Histidine and arginine are associated with inflammation and oxidative stress in obese women. Br. J. Nutr. 2012;108:57–61. doi: 10.1017/S0007114511005289. PubMed DOI

Okubo H., Sasaki S. Histidine intake may negatively correlate with energy intake in human: A cross-sectional study in Japanese female students aged 18 years. J. Nutr. Sci. Vitaminol. (Tokyo) 2005;51:329–334. doi: 10.3177/jnsv.51.329. PubMed DOI

Li Y.-C., Li C.-L., Qi J.-Y., Huang L.-N., Shi D., Du S.-S., Liu L.-Y., Feng R.-N., Sun C.-H. Relationships of dietary histidine and obesity in northern Chinese adults, an internet-based cross-sectional study. Nutrients. 2016;8:420. doi: 10.3390/nu8070420. PubMed DOI PMC

Gerber D.A. Low free serum histidine concentration in rheumatoid arthritis. A measure of disease activity. J. Clin. Investig. 1975;55:1164–1173. doi: 10.1172/JCI108033. PubMed DOI PMC

Sitton N.G., Dixon J.S., Astbury C., Francis R.J., Bird H.A., Wright V. Kinetic investigations into the possible cause of low serum histidine in rheumatoid arthritis. Ann. Rheum. Dis. 1988;47:48–52. doi: 10.1136/ard.47.1.48. PubMed DOI PMC

Andou A., Hisamatsu T., Okamoto S., Chinen H., Kamada N., Kobayashi T., Hashimoto M., Okutsu T., Shimbo K., Takeda T., et al. Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages. Gastroenterology. 2009;136:564–574.e2. doi: 10.1053/j.gastro.2008.09.062. PubMed DOI

Ishihara R., Iishi H., Sakai N., Yano H., Uedo N., Narahara H., Iseki K., Mikuni T., Ishiguro S., Tatsuta M. Polaprezinc attenuates Helicobacter pylori-associated gastritis in Mongolian gerbils. Helicobacter. 2002;7:384–389. doi: 10.1046/j.1523-5378.2002.00114.x. PubMed DOI

Hisamatsu T., Ono N., Imaizumi A., Mori M., Suzuki H., Uo M., Hashimoto M., Naganuma M., Matsuoka K., Mizuno S., et al. Decreased plasma histidine level predicts risk of relapse in patients with ulcerative colitis in remission. PLoS ONE. 2015;10:e01407166. doi: 10.1371/journal.pone.0140716. PubMed DOI PMC

Kanarek N., Keys H.R., Cantor J.R., Lewis C.A., Chan S.H., Kunchok T., Abu-Remaileh M., Freinkman E., Schweitzer L.D., Sabatini D.M. Histidine catabolism is a major determinant of methotrexate sensitivity. Nature. 2018;559:632–636. doi: 10.1038/s41586-018-0316-7. PubMed DOI PMC

Palmer C.N., Irvine A.D., Terron-Kwiatkowski A., Zhao Y., Liao H., Lee S.P., Goudie D.R., Sandilands A., Campbell L.E., Smith F.J., et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet. 2006;38:441–446. doi: 10.1038/ng1767. PubMed DOI

Scott I.R., Harding C.R., Barrett J.G. Histidine-rich protein of the keratohyalin granules. Source of the free amino acids, urocanic acid and pyrrolidone carboxylic acid in the stratum corneum. Biochim. Biophys. Acta. 1982;719:110–117. doi: 10.1016/0304-4165(82)90314-2. PubMed DOI

Jontofsohn R., Heinze V., Katz N., Stuber U., Wilke H., Kluthe R. Histidine and iron supplementation in dialysis and pre-dialysis patients. Proc. Eur. Dial. Transplant. Assoc. 1975;11:391–397. PubMed

Blumenkrantz M.J., Shapiro D.J., Swendseid M.E., Kopple J.D. Histidine supplementation for treatment of anaemia of uraemia. Br. Med. J. 1975;2:530–533. doi: 10.1136/bmj.2.5970.530. PubMed DOI PMC

Phillips M., Politis-Tsegos C., de Wardener H. Letter: Histidine for treatment of uraemic anaemia. Br. Med. J. 1974;1:517. doi: 10.1136/bmj.1.5906.517-b. PubMed DOI PMC

Berns J.S., Mosenkis A. Pharmacologic adjuvants to epoetin in the treatment of anemia in patients on hemodialysis. Hemodial. Int. 2005;9:7–22. doi: 10.1111/j.1492-7535.2005.01113.x. PubMed DOI

Vera-Aviles M., Vantana E., Kardinasari E., Koh N.L., Latunde-Dada G.O. Protective role of histidine supplementation against oxidative stress damage in the management of anemia of chronic kidney disease. Pharmaceuticals (Basel). 2018;11:E111. doi: 10.3390/ph11040111. PubMed DOI PMC

Sato M., Karasawa N., Shimizu M., Morimatsu F., Yamada R. Safety evaluation of chicken breast extract containing carnosine and anserine. Food Chem. Toxicol. 2008;46:480–489. doi: 10.1016/j.fct.2007.08.020. PubMed DOI

Geliebter A.A., Hashim S.A., Van Itallie T.B. Oral L-histidine fails to reduce taste and smell acuity but induces anorexia and urinary zinc excretion. Am. J. Clin. Nutr. 1981;34:119–120. doi: 10.1093/ajcn/34.1.119. PubMed DOI

Henkin R.I., Patten B.M., Re P.K., Bronzert D.A. A syndrome of acute zinc loss. Cerebellar dysfunction, mental changes, anorexia, and taste and smell dysfunction. Arch. Neurol. 1975;32:745–751. doi: 10.1001/archneur.1975.00490530067006. PubMed DOI

Solomon J.K., Geison R.L. Effect of excess dietary L-histidine on plasma cholesterol levels in weanling rats. J. Nutr. 1978;108:936–943. doi: 10.1093/jn/108.6.936. PubMed DOI

Harvey P.W., Hunsaker H.A., Allen K.G. Dietary L-histidine-induced hypercholesterolemia and hypocupremia in the rat. J. Nutr. 1981;111:639–647. doi: 10.1093/jn/111.4.639. PubMed DOI

Hitomi-Ohmura E., Amano N., Aoyama Y., Yoshida A. The effect of a histidine-excess diet on cholesterol synthesis and degradation in rats. Lipids. 1992;27:755–760. doi: 10.1007/BF02535845. PubMed DOI

Holeček M., Vodeničarovová M. Effects of histidine supplementation on amino acid metabolism in rats. Physiol. Res. 2020;69:99–111. PubMed PMC

Tyfield L.A., Holton J.B. The effect of high concentrations of histidine on the level of other amino acids in plasma and brain of the mature rat. J. Neurochem. 1976;26:101–105. PubMed

Teloh J.K., Dohle D.-S., Petersen M., Verhaegh R., Waack I.N., Roehrborn F., Jakob H., de Groot H. Histidine and other amino acids in blood and urine after administration of Bretschneider solution (HTK) for cardioplegic arrest in patients: Effects on N-metabolism. Amino Acids. 2016;48:1423–1432. doi: 10.1007/s00726-016-2195-2. PubMed DOI PMC

Du S., Sun S., Liu L., Zhang Q., Guo F., Li C., Feng R., Sun C. Effects of histidine supplementation on global serum and urine 1H NMR-based metabolomics and serum amino acid profiles in obese women from a randomized controlled study. J. Proteome Res. 2017;16:2221–2230. doi: 10.1021/acs.jproteome.7b00030. PubMed DOI

Circulating Metabolites in Relation to the Kidney Allograft Function in Posttransplant Patients

Side effects of amino acid supplements