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Absorption and distribution

L-histidine is one of the 20 standard proteinogenic amino acids present in proteins of all living organisms (Kulis-Horn et al., 2014, Microbial Biotechnology 7 (1), 5–25). It is an essential α-amino acid for humans and other mammals, while initially it was thought to be only essential for infants (Kopple and Swendseid, 1975, Journal of Clinical Investigation 55 (5): 881–91).


L-histidine is biosynthesized by archaea (Lee et al.,2008, J Bacteriol 190, 2629–2632), Gram-positive bacteria (Chapman and Nester, 1969, Bacillus subtilis. J Bacteriol 97, 444–1448), lower eukaryotes (Fink, 1964, Science, 146, 525 -527), and plants (Stepansky and Leustek, 2006, Amino Acids 30,127–142).

Because its side arm is a positively charged imidazole ring, L-histidine has aromatic properties (Kulis-Horn et al., 2014,Microbial Biotechnology 7 (1), 5–25). Also, it is the only amino acid whose side-chain can switch from an unprotonated to a protonated state under neutral pH conditions due to the pKa value of 6.0 of its side-chain (Nelson and Cox, 2009,Lehninger Biochemie, Springer,Berlin, Germany). This characteristic enables L-histidine residues to act as both, a proton acceptor or a proton donor, in many cellular enzymatic reactions (Rebek, 1990,Struct Chem, 1,129–131; Polgár, 2005,Cell Mol Life Sci, 62,2161–2172).


L-histidine must predominantly be taken up through the diet. Humans can obtain histidine through the breakdown of carnosine via the action of carnosine dipeptidase, however, this is limited. Therefore, it is considered to be one of the essential amino acids (Bakardjiev and Bauer, 2000, Biochemistry, 65, 779-782).

Preliminary predictions of adsorption of a substance can be made from its physico-chemical properties (“Toxicological risk assessment of chemicals, a practical guide” (Nielsen E. et al, Informa healthcare, New York, London, 2008). Since the Log Kow is -3.32 and the water solubility is 43 g/kg, L-Histidine is clearly hydrophilic and very soluble in water. Regarding inhalation, the combination of low volatility, a negative Log Kow and high water solubility suggests that absorption directly across the respiratory tract epithelium is unlikely.

Oral absorption is very favourable for L-histidine since the substance has a low molecular weight, is very hydrophilic and very soluble in water. L-histidine will readily dissolve in the gastrointestinal fluids and absorption can occur along the entire gastrointestinal tract and will be high.

Dermal absorption is unlikely because the poor lipophilicity suggests that substance is not likely to cross the stratum corneum. Moreover, the low volatility in combination with the high water solubility and the negative Log P value indicate that the substance may be too hydrophilic to cross the lipid rich stratum corneum and thus dermal uptake will be unlikely. (Nielasen et al., 2010, Informa Healthcare, Telephone House, London, UK)

L-histidine is thus absorbed from the gastro-intestinal tract. Subsequently, L-histidine is transported to the liver and used as protein building blocks.


An increased intake of L-histidine can cause a copper deficiency, because it inhibits the absorption of copper. Also, L-histidine can enhance the uptake of minerals, such as zinc. Supplementation of histidine has been shown to cause rapid zinc excretion in rats with an excretion rate 3 to 6 times higher than normal (Freeman and Taylor, 1977, The American Journal of Clinical Nutrition, 30 (4), 523 -527;Wensink et al., 1988, Biological Trace Element Research, 16(2), 137–50).



While only adult humans can synthesize histidine, all humans can metabolize histidine. L-histidine is involved in the formation of proteins and influences several metabolic reactions in the body.

First, L-histidine is a precursor for histamine. Through decarboxylation of L-histidine histamine is formed (Darvas and Falus, 2004, In Falus A (ed), SpringMed Publishing, Budapest). Histamine is an important mediator of many biological processes including inflammation, gastric acid secretion, neuromodulation, and regulation of immune function. The release of histamine into the circulation causes bronchoconstriction and vasodialtion which are the general symptoms associated with asthma and various allergic reactions.

(Nelson and Cox, 2005, Lehninger, New York)

Secondly, L-histidine is used in the biosynthesis of carnosine (Bakardjiev and Bauer, 2000,Biochemistry, Moscow, 65 (7), 779-782). The latteracts as a scavenger of reactive oxygen species, and has anti-apoptotic effects (Boldyrev et al., 1999, Neuroscience, 94, 571-577).

Thirdly, L-histidine is important inhaemoglobin. It assists in stabilising oxyhaemoglobin and destabilises CO-bound haemoglobin. As a result,CO cannot adopt the proper angle to form a strong hydrogen bond with the distal histidine(Olson and Phillips, 1997, JBIC, 2, 544-552.).

Lastly, through the catabolism of L-histidine, it can be converted to glutamate, which is an intermediate of thecitric acid cycle (Thauer, 1988, Eur. J. Biochem. 176, 497-508).Because the end product is glutamate, L-histidine is one of the glucogenic amino acids (Nelson and Cox, 2005, Lehninger, New York).



Catabolism of amino acids is particularly critical to the survival of animals with high-protein diets or during starvation.

L-histidine can be converted to histamine and once histamine is generated it can be converted to several breakdown products including N-methylhistamine, imidazole acetaldehyde, methylimidazole acetaldehyde and methylimidazole-acetic acid (Nelson and Cox, 2005, Lehninger, New York; Salway, 2004, Blackwell Science Ltd, Alden, Mass)


L-histidine catabolism begins with the release of the α-amino group catalyzed by histidase, leading to the deaminated product, urocanate. Urocanate is converted to 4-imidazolone-5-propionate via the action of urocanate hydratase. The latter product is then converted to N-formiminoglutamte via the action of imidazolone propionase. The enzyme formiminotransferase cyclodeaminase then removes the formimino group to yield glutamate. Glutamate can be converted to α-ketoglutarate and in this way will enter the citric acid cycle, as described above. The end product glutamate can also enter the urea cycle through carbamoyl phosphate and in this way beexcreted as urea in the urine.(Nelson and Cox, 2005, Lehninger, New York; Salway, 2004, Blackwell Science Ltd, Alden, Mass)