Histidine Articles 1

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Human urinary excretion of L-histidine-related compounds after ingestion of several meats and fish muscle

            (Abe, Okuma et al. 1993) Download

1. After oral administration of the muscle of skipjack tuna, about 90% of ingested anserine (Ans) was excreted quickly into urine as Ans (8%) and pi-methylHis (82%), indicating the fast decomposition of Ans into pi-methylHis. This was also the case for chicken muscle ingestion. 2. After eel muscle ingestion, carnosine (Car) excretion was only 1% of the ingested whereas almost no increase was found in His, a constituent of Car, indicating the re-utilization of this essential amino acid. Similar results were also obtained from beef and pork ingestion. 3. In all cases, the urinary excretion of these compounds reached a maximum within 7 hr after ingestion and returned to the level of meat-free diet within 40 hr.

Histidine supplementation for treatment of anaemia of uraemia

            (Blumenkrantz, Shapiro et al. 1975) Download

The effects of supplemental histidine on the anaemia of 16 chronically uraemic patients and 26 patients undergoing maintenance dialysis were assessed. Patients were given either L-histidine 4 g/day or placebo for a mean of 17-5 weeks in a randomized double-blind controlled study. Haemoglobin and packed cell volume increased slightly and to a similar degree in the patients on dialysis receiving placebo and histidine, but this change was statistically significant only in those on placebo. Plasma histidine rose significantly in the histidine-treated patients undergoing dialysis and decreased in the uraemic patients receiving placebo. These results suggest that supplementary L-histidine in patients with uraemia or patients undergoing maintenance dialysis does not improve anaemia.

Effects of L-histidine on hydrogen peroxide-induced DNA damage and cytotoxicity in cultured mammalian cells

            (Cantoni, Sestili et al. 1992) Download

L-Histidine markedly increased the growth- and DNA synthesis-inhibitory effects elicited by hydrogen peroxide in cultured Chinese hamster ovary cells. DNA single-strand breakage was also higher in the presence of the amino acid and, in addition, these breaks were characterized by a slower rate of repair, compared with that of the breaks generated by the oxidant alone. In the presence of L-histidine, hydrogen peroxide also produced DNA double-strand breakage, a lesion that cannot be detected in cells treated with even exceedingly high concentrations of the oxidant alone. Data reported herein suggest that the L-histidine-mediated increase of the cytotoxic response of cultured Chinese hamster ovary cells to hydrogen peroxide may be at least partially dependent on the formation of DNA double-strand breaks.

L-histidine inhibits production of lysophosphatidic acid by the tumor-associated cytokine, autotaxin

            (Clair, Koh et al. 2005) Download

BACKGROUND: Autotaxin (ATX, NPP-2), originally purified as a potent tumor cell motility factor, is now known to be the long-sought plasma lysophospholipase D (LPLD). The integrity of the enzymatic active site, including three crucial histidine moieties, is required for motility stimulation, as well as LPLD and 5'nucleotide phosphodiesterase (PDE) activities. Except for relatively non-specific chelation agents, there are no known inhibitors of the ATX LPLD activity. RESULTS: We show that millimolar concentrations of L-histidine inhibit ATX-stimulated but not LPA-stimulated motility in two tumor cell lines, as well as inhibiting enzymatic activities. Inhibition is reversed by 20-fold lower concentrations of zinc salt. L-histidine has no significant effect on the Km of LPLD, but reduces the Vmax by greater than 50%, acting as a non-competitive inhibitor. Several histidine analogs also inhibit the LPLD activity of ATX; however, none has greater potency than L-histidine and all decrease cell viability or adhesion. CONCLUSION: L-histidine inhibition of LPLD is not a simple stoichiometric chelation of metal ions but is more likely a complex interaction with a variety of moieties, including the metal cation, at or near the active site. The inhibitory effect of L-histidine requires all three major functional groups of histidine: the alpha amino group, the alpha carboxyl group, and the metal-binding imidazole side chain. Because of LPA's involvement in pathological processes, regulation of its formation by ATX may give insight into possible novel therapeutic approaches.

Dietary L-histidine regulates murine skin levels of trans-urocanic acid, an immune-regulating photoreceptor, with an unanticipated modulation: potential relevance to skin cancer

            (De Fabo, Webber et al. 1997) Download

Solar ultraviolet-B radiation (UVB; 290-320 nm) causes skin cancer and suppresses cell-mediated immunity, preventing the rejection of UV-induced tumors. One mechanism initiating UV suppression involves the trans to cis photoisomerization of urocanic acid (UCA), a histidine derivative found in the stratum corneum. The addition of L-histidine to nonpurified mouse diet has been shown to increase skin trans-UCA levels and sensitivity to UVB immune suppression. Specially formulated L-histidine diets (0.40-64 g/kg) fed to BALB/c mice that were monitored over a 19-wk period resulted in an unexpected modulation of skin trans-UCA. ANOVA revealed a group-time interaction, providing initial evidence that the skin levels of trans-UCA were modulating up and down in all groups except the control group (6.4 g/kg diet). We observed that both high (64 g/kg diet) and low (0.4 g/kg diet) levels of dietary L-histidine resulted in the increase of skin trans-UCA to levels significantly higher than those recorded in the control group. In mice fed these histidine levels, skin trans-UCA increased to between 2.9 and 3.6 nmol/mg skin (64 g/kg diet, over 5 wk; 0.4 g/kg diet, over 8 wk) and then decreased to approximately 1.69 nmol/mg skin, the base-line level (64 g/kg diet, over 11 wk; 0.4 g/kg diet, over 17 wk). The increase in trans-UCA levels in mice with low L-histidine intake may be the result of protein malnutrition, consistent with weight loss observed in those mice. The modulation of trans-UCA levels in skin by dietary L-histidine has not been previously described; its role in skin cancer development is under investigation.

Urinary histidine excretion in patients with classical allergy (type a allergy), food intolerance (type b allergy), and fungal-type dysbiosis

            (Eaton, Howard et al. 1998) Download

Changes in histidine excretion reflect histidine conservation and thus the level of histamine secretion. Low levels were found in untreated patients with atopic (type A) allergy. However, levels in food intolerance (type B allergy) and fungal-type dysbiosis were also low (P < 0.001 for each group compared with nonallergic controls). There were no differences between the three groups. The biochemical and clinical significance of these findings is discussed.

The histamine H3 receptor: an attractive target for the treatment of cognitive disorders

            (Esbenshade, Browman et al. 2008) Download

The histamine H3 receptor, first described in 1983 as a histamine autoreceptor and later shown to also function as a heteroreceptor that regulates the release of other neurotransmitters, has been the focus of research by numerous laboratories as it represents an attractive drug target for a number of indications including cognition. The purpose of this review is to acquaint the reader with the current understanding of H3 receptor localization and function as a modulator of neurotransmitter release and its effects on cognitive processes, as well as to provide an update on selected H3 antagonists in various states of preclinical and clinical advancement. Blockade of centrally localized H3 receptors by selective H3 receptor antagonists has been shown to enhance the release of neurotransmitters such as histamine, ACh, dopamine and norepinephrine, among others, which play important roles in cognitive processes. The cognitive-enhancing effects of H3 antagonists across multiple cognitive domains in a wide number of preclinical cognition models also bolster confidence in this therapeutic approach for the treatment of attention deficit hyperactivity disorder, Alzheimer's disease and schizophrenia. However, although a number of clinical studies examining the efficacy of H3 receptor antagonists for a variety of cognitive disorders are currently underway, no clinical proof of concept for an H3 receptor antagonist has been reported to date. The discovery of effective H3 antagonists as therapeutic agents for the novel treatment of cognitive disorders will only be accomplished through continued research efforts that further our insights into the functions of the H3 receptor.

Pharmacological properties of ABT-239 [4-(2-(Fox, Esbenshade et al.)-benzofuran-5-yl)benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist

            (Fox, Esbenshade et al. 2005) Download

Influence of histidine administration on zinc metabolism in the rat

            (Freeman and Taylor 1977) Download

The influence of intravenous and oral histidine administration on zinc metabolism in the rat has been investigated. Acute studies: histidine (250 mg/hr) was given by constant intravenous infusion to rats with paired control animals receiving diluent alone. During the hour preceding histidine the urinary zinc excretion averaged 0.435 +/- 0.37 (SE) microng/hr. During the hours of histidine infusion the urinary zinc excretion averaged 7.58 +/- 0.97, 20.21 +/- 2.07, and 16.78 +/- 1.90 microng/hr. These values were all higher than the prehistidine infusion value and higher than in the rats receiving diluent alone. Plasma zinc at the end of the infusion was 76 +/- 5 microng/100 ml compared to control levels of 110 +/- 9 microng/100 ml, P less than 0.001. Chronic studies: histidine (500 mg/day) was given by gavage for 43 days to rats. Urinary zinc excretion in histidine treated rats was 3 to 6 times that of controls throughout the study. Despite this there was no difference in the plasma, testicular, or kidney zinc content. No histological lesions of zinc deficiency were noted in the esophagus. In conclusion, histidine increased urinary excretion in the rats whether administered orally or parenterally. Evidence for zinc deficiency, however, was not apparent after 43 days of histidine administration.


Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma

            (Karrlander, Lindberg et al. 2009) Download

Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the modest efficacy of these drugs and emerging problems with anti-VEGF treatment resistance welcome the development of alternative antiangiogenic therapies. One potential candidate is histidine-rich glycoprotein (HRG), a plasma protein with antiangiogenic properties that can inhibit endothelial cell adhesion and migration. We have used the RCAS/TV-A mouse model for gliomas to investigate the effect of HRG on brain tumor development. Tumors were induced with platelet-derived growth factor-B (PDGF-B), in the presence or absence of HRG. We found that HRG had little effect on tumor incidence but could significantly inhibit the development of malignant glioma and completely prevent the occurrence of grade IV tumors (glioblastoma).

Supplementation with L-histidine during dietary zinc repletion improves short-term memory in zinc-restricted young adult male rats

            (Keller, Chu et al. 2000) Download

Zinc, an essential dietary element, modulates neurotransmission in brain regions associated with cognition. Cognitive dysfunction has been reported in offspring of female rats fed zinc-restricted diets during gestation and/or lactation. Studies on the cognitive effects of zinc restriction during young adulthood are limited. After a 3-wk period of dietary zinc restriction, male rats (71-75 d old) were repleted with zinc chloride alone, or zinc chloride supplemented with L-histidine, and short-term memory was measured using the Morris water maze. During restriction, zinc-restricted rats demonstrated significantly longer (86.0%) retrieval latencies than nonrestricted controls, and significantly lower liver (25.5%), bone (32.5%) and hippocampal (3.2%) zinc concentrations. During subsequent repletion, rats repleted with zinc chloride supplemented with L-histidine improved their retrieval latencies to the extent that they were no longer significantly different from controls by repletion d 3. This was associated with a return of hippocampal zinc concentrations to control values by repletion d 3. The mean retrieval escape latencies of the zinc chloride-repleted rats remained significantly prolonged (75.0%). Collectively, these data indicate the following: 1) feeding a zinc-restricted diet for 3 wk impairs short-term memory in young adult male rats, and 2) repletion with dietary zinc supplemented with L-histidine improves short-term memory function more efficiently than dietary zinc chloride alone. The latter point suggests that dietary zinc supplemented with L-histidine is more bioavailable to the brain than zinc provided as zinc chloride alone. These findings are important in that they highlight the importance of both dietary zinc formulation and the use of functional assessments in determining zinc nutriture.

Brain histamine in experimental acute liver failure: effects of L-histidine loading

            (Lozeva-Thomas, Ahonen et al. 2004) Download

The biological activity of hydrogen peroxide. VI. Mechanism of the enhancing effects of L-histidine: the role of the formation of a histidine-peroxide adduct and membrane transport

            (Oya-Ohta, Ochi et al. 1995) Download

Further details of the mechanism of the enhancing effects of L-histidine (L-His) on the clastogenic activities of hydrogen peroxide (H2O2) were investigated. The L-His-H2O2 adduct was prepared and its physicochemical properties and biological activities were compared with those of a mixture of L-His plus H2O2 and of H2O2 alone. When the stabilities of the three test samples against glucose were determined in terms of residual H2O2 content in solutions of various pH values over the course of 11 days, the adduct was found to be more stable than H2O2 alone and very similar in terms of stability to the mixture. The almost equivalent stability of the adduct and the mixture suggested formation of the adduct in the mixture even though the interaction between L-His and H2O2 in solution seems, from 13C-NMR analysis, to be rather weak. In cell-free DNA after lysis of cell membranes, the induction of single-strand breaks (SSB) by the adduct and by the mixture was less effective than by H2O2 alone. These results contrast with previous results obtained in intact cells (Oya et al., 1992) and demonstrate the indispensability of the cell membrane for the enhancing effects of L-His. In the presence of inhibitors of the active transport of L-His, namely, 10 different neutral amino acids, effective suppression of the clastogenic activity of the adduct and of the mixture was observed, whereas four acidic and basic amino acids had no effect. Thus, the participation of active transport in the enhancing effects of L-His was apparent. The formation of the adduct of L-His with H2O2 brings about the stabilization or reduces the reactivity of H2O2 and, as a result, the induction of SSB is prevented to some extent in cell-free DNA systems. By contrast, in a cellular system, the accumulation of the adduct in cells by active transport is potentiated by the enhancing effect of L-His, although the mediation of some factors that can generate hydroxyl radicals (*OH) from the adduct in cells must be postulated.


 Antidiarrheal effects of L-histidine-supplemented rice-based oral rehydration solution in the treatment of male adults with severe cholera in Bangladesh: a double-blind, randomized trial

            (Rabbani, Sack et al. 2005) Download

BACKGROUND: Because of the antisecretory potential of L-histidine in the intestinal tract, its antidiarrheal effects were determined in cholera. METHODS: In a double-blind trial of 126 adult male patients with cholera, L-histidine (2.5 g/L) was mixed with a rice-based oral rehydration solution (ORS) and administered to 62 patients; 64 patients received the same ORS without L-histidine. All patients received ciprofloxacin at a dosage of 500 mg every 12 h for 72 h. Fluid output (of stool, urine, and vomit) and intake (of ORS, water, and intravenous fluid) were determined every 8 h for 72 h. RESULTS: Administration of ORS with L-histidine significantly (P<.05) reduced the frequency of stool output during 32-64 h after initiation of ORS treatment, compared with that in patients given ORS without L-histidine ([all data are means+/-SD] 32-48 h, 11.5+/-6.9 mL/kg vs. 18.8+/-16.0 mL/kg; 40-48 h, 6.7+/-4.4 mL/kg vs. 11.5+/-9.7 mL/kg; and 56-64 h, 6.3+/-5.8 mL/kg vs. 7.8+/-4.1 mL/kg). An overall reduction of 22% in the volume of stool was observed in patients given ORS without L-histidine. The amount of required unscheduled intravenous fluid was lower in patients given ORS with L-histidine, compared with that in patients given ORS without L-histidine (0-24 h, 82.5+/-44.4 mL/kg vs. 158.6+/-72.2 mL/kg [P<.01]; and 24-48 h, 41.6+/-40.4 mL/kg vs. 52.5+/-22.1 mL/kg [P>.05]). Administration of ORS with L-histidine also significantly reduced (P<.05) the intake of ORS and the duration of illness. No adverse effects were observed in these patients. CONCLUSIONS: L-histidine reduces the weight of stool and the frequency of stool output in cholera and could be a useful and safe adjunct treatment that will increase the success rate of ORS and antibiotic therapy in cholera.

Failure of histidine supplementation to improve anemia in chronic dialysis patients

            (Reeves, Barbour et al. 1977) Download

Failure of histidien supplementation to improve anemia in chronic dialysis patients was seen in six patients after a study period of 8 weeks. Serum amino acid levels were elevated to normal by supplementation with 1 g of oral histidine/day in all patients. There was no significant change in serum iron or transferrin levels, hematocrit, or red cell mass in five of the six patients. Histidine supplementation may raise serum amino acid levels, but does not cause any increase in red cell mass or improve the anemia in patients on chronic dialysis who are ingesting adequate dietary protein.


The Histidine Treatment of Peptic Ulcer of the Lesser Curvature: With a Note on Twelve Cases

            (Smith 1935) Download

Oral L-histidine exerts antihypertensive effects via central histamine H3 receptors and decreases nitric oxide content in the rostral ventrolateral medulla in spontaneously hypertensive rats

            (Toba, Nakamori et al. 2010) Download

1. L-histidine is generally found in meat, poultry and fish. To investigate its effects on blood pressure, L-histidine was administered to 9-week-old spontaneously hypertensive rats (SHR). 2. Oral administration of L-histidine (100 mg / kg) increased histamine content in cerebrospinal fluid and reduced mean arterial pressure (MAP) in SHR. Intracerebroventricular injection of L-histidine (0.01 microg / 5 microL) also caused a decrease in MAP, which was reversed by cotreatment with the histamine H3 receptor antagonist thioperamide (20.4 microg / 5 microL, i.c.v.). There was a significant, time-dependent increase (over 6 h) in the NOx (NO2- + NO3-) content of the dialysate from the rostral ventrolateral medulla (RVLM), a major vasomotor centre, after oral administration of L-histidine. 3. In another experiment, SHR were treated with l-histidine (100 mg / kg) twice a day for 4 weeks. Chronic treatment with L-histidine inhibited the age-dependent increases in systolic blood pressure and urinary noradrenaline excretion seen in vehicle-treated SHR. Conversely, intracerebroventricular injection of thioperamide (20.4 microg / 5 microL, i.c.v.) reversed the decrease in MAP in response to L-histidine in SHR. 4. Reverse transcription-polymerase chain reaction analysis revealed that the aortic expression of angiotensin-converting enzyme mRNA was suppressed by chronic treatment with L-histidine. 5. These results suggest that L-histidine decreases blood pressure by attenuating sympathetic output via the central histamine H3 receptor in SHR. In addition, the antihypertensive effects of L-histidine appear to be associated with an increase in nitric oxide in the RVLM.

Histidine Treatment of Peptic Ulcer

            (Wingfield 1936) Download

The Effect of Histidine on the Experimental Production of Peptic Ulcer

            (Wu 1937) Download


References

Abe, H., E. Okuma, et al. (1993). "Human urinary excretion of L-histidine-related compounds after ingestion of several meats and fish muscle." Int J Biochem 25(9): 1245-9.

Ai, W., S. Takaishi, et al. (2006). "Regulation of L-histidine decarboxylase and its role in carcinogenesis." Prog Nucleic Acid Res Mol Biol 81: 231-70.

Blumenkrantz, M. J., D. J. Shapiro, et al. (1975). "Histidine supplementation for treatment of anaemia of uraemia." Br Med J 2(5970): 530-3.

Cantoni, O., P. Sestili, et al. (1992). "Effects of L-histidine on hydrogen peroxide-induced DNA damage and cytotoxicity in cultured mammalian cells." Mol Pharmacol 41(5): 969-74.

Clair, T., E. Koh, et al. (2005). "L-histidine inhibits production of lysophosphatidic acid by the tumor-associated cytokine, autotaxin." Lipids Health Dis 4: 5.

De Fabo, E. C., L. J. Webber, et al. (1997). "Dietary L-histidine regulates murine skin levels of trans-urocanic acid, an immune-regulating photoreceptor, with an unanticipated modulation: potential relevance to skin cancer." J Nutr 127(11): 2158-64.

Eaton, K. K., M. Howard, et al. (1998). "Urinary histidine excretion in patients with classical allergy (type a allergy), food intolerance (type b allergy), and fungal-type dysbiosis." J Nutritional Biochemistry 9(10): 586–590.

Ercan-Sencicek, A. G., A. A. Stillman, et al. (2010). "L-histidine decarboxylase and Tourette's syndrome." N Engl J Med 362(20): 1901-8.

Esbenshade, T. A., K. E. Browman, et al. (2008). "The histamine H3 receptor: an attractive target for the treatment of cognitive disorders." Br J Pharmacol 154(6): 1166-81.

Fox, G. B., T. A. Esbenshade, et al. (2005). "Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist." J Pharmacol Exp Ther 313(1): 176-90.

Freeman, R. M. and P. R. Taylor (1977). "Influence of histidine administration on zinc metabolism in the rat." Am J Clin Nutr 30(4): 523-7.

Karrlander, M., N. Lindberg, et al. (2009). "Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma." PLoS One 4(12): e8536.

Keller, K. A., Y. Chu, et al. (2000). "Supplementation with L-histidine during dietary zinc repletion improves short-term memory in zinc-restricted young adult male rats." J Nutr 130(6): 1633-40.

Lozeva-Thomas, V., P. Ahonen, et al. (2004). "Brain histamine in experimental acute liver failure: effects of L-histidine loading." Inflamm Res 53 Suppl 1: S55-6.

Oya-Ohta, Y., T. Ochi, et al. (1995). "The biological activity of hydrogen peroxide. VI. Mechanism of the enhancing effects of L-histidine: the role of the formation of a histidine-peroxide adduct and membrane transport." Mutat Res 326(1): 99-107.

Pap, E., K. Racz, et al. (2002). "Histidine decarboxylase deficiency in gene knockout mice elevates male sex steroid production." J Endocrinol 175(1): 193-9.

Rabbani, G. H., D. A. Sack, et al. (2005). "Antidiarrheal effects of L-histidine-supplemented rice-based oral rehydration solution in the treatment of male adults with severe cholera in Bangladesh: a double-blind, randomized trial." J Infect Dis 191(9): 1507-14.

Reeves, R. D., G. L. Barbour, et al. (1977). "Failure of histidine supplementation to improve anemia in chronic dialysis patients." Am J Clin Nutr 30(4): 579-81.

Skoldberg, F., G. M. Portela-Gomes, et al. (2003). "Histidine decarboxylase, a pyridoxal phosphate-dependent enzyme, is an autoantigen of gastric enterochromaffin-like cells." J Clin Endocrinol Metab 88(4): 1445-52.

Smith, D. (1935). "The Histidine Treatment of Peptic Ulcer of the Lesser Curvature: With a Note on Twelve Cases." Br Med J 2(3890): 154-159.

Tanaka, S., K. Hamada, et al. (2002). "Gastric acid secretion in L-histidine decarboxylase-deficient mice." Gastroenterology 122(1): 145-55.

Toba, H., A. Nakamori, et al. (2010). "Oral L-histidine exerts antihypertensive effects via central histamine H3 receptors and decreases nitric oxide content in the rostral ventrolateral medulla in spontaneously hypertensive rats." Clin Exp Pharmacol Physiol 37(1): 62-8.

Wingfield, A. (1936). "Histidine Treatment of Peptic Ulcer." Br Med J 1(3935): 1156-1158.

Wu, P. P. (1937). "The Effect of Histidine on the Experimental Production of Peptic Ulcer." Ann Surg 106(2): 196-9.