Imidazoleacetic Acid Research Articles

Imidazoleacetic acid excretion in guinea-pigs adapted to histamine

The excretion of imidazoleacetic acid (ImAA) was examined in the urine of guinea-pigs treated daily for 8–12 weeks with histamine aerosols (adapted guinea-pigs). In histamine-adapted animals tested 8 days after the last exposure to histamine aerosol, the urinary excretion of ImAA was higher than in normal ones. However, in contrast to normal animals any additional inhalation of histamine produced a marked decrease in ImAA excretion. The inhibitory action of excessive amounts of histamine on diamine oxidase (DAO) (EC. 1.4.3.6) activity and therefore ImAA excretion may depend on the formation of a condensation product of histamine with pyridoxal phosphate. The role of the inhibitory action of an excess of histamine on the original metabolic pathway of histamine degradation is discussed.

Histamine metabolism in invertebrates

1. 1. The metabolism of histamine (ring-2-C 14) dihydrochloride by muscle and nervous tissue from crabs, snails and cockroaches was compared. 2. 2. Imidazoleacetic acid and an unknown compound (C) were formed by both tissues in all three species in vitro. 3. 3. Acetylhistamine was only produced by the cockroach. 4. 4. Methylhistamine was not detected as a product of histamine metabolism in muscle or nerve of any of the animals examined.

Histamine Metabolism in Healthy Subjects before and during Treatment with Aminoguanidine

Three healthy subjects were given intravenous infusions of 14C-histamine, one infusion before and another during aminoguanidine treatment. Urine was analyzed for 14C-histamine and its radioactive metabolites, and also for total histamine, methylhistamine, and methyl-imidazoleacetic acid. The general metabolic patterns of exogenous (radioactive) and endogenous (non-radioactive) histamine were found to be qualitatively similar. Aminoguanidine treatment a) abolished the excretion of radioactive imidazoleacetic acid, b) increased the excretion of both radioactive methylhistamine and total methylhistamine, c) had little effect on the excretion of histamine and methylimidazoleacetic acid. Some evidence was obtained for impaired oxidation of methylhistamine during aminoguanidine treatment. The informative value of measurements of histamine, methylhistamine and methylimidazoleacetic acid in human urine under different conditions is discussed.

Histidine Metabolism in the Human Adult: Histidine blood tolerance, and the effect of continued free L-histidine ingestion on the concentration of imidazole compounds in blood and urine

Relationships among the intermediary metabolites of histidine were studied in the human adult. Histidine and imidazolelactic acid were the only imidazole compounds identified in the fasting plasma of 3 healthy human adults fed a constant diet. Plasma histidine tolerance studies in which 5 g of L-histidine (free base) were fed, showed the peak increase in histidine to occur one hour after ingestion; imidazolelactic acid changes paralleled that of histidine. Eleven imidazole compounds were quantitatively identified in 24-hour urine samples collected for periods of 3 consecutive days before histidine ingestion, during ingestion of a 10-g daily load of free L-histidine, and after histidine ingestion. Histidine loading caused an increase in the excretion of histidine, urocanic acid, imidazolepropionic acid, imidazoleacetic acid and imidazolelactic acid; none of these returned to the pre-histidine ingestion level by the end of the 3-day post-histidine period. The amounts of 4-amino-5-imidazole carboxamide, carnosine, homocarnosine, anserine, 1-methylhistidine, and 3-methylhistidine either were not affected by histidine loading, or the results were erratic and varied among the subjects.

Synthesis of α-tritiated L-histidine, L-arginine and L-lysine

Tritium was introduced into the alpha position of histidine, arginine, and lysine by racemization using the azlactone rearrangement in an anhydrous tritiated medium. The monoacetyl derivatives of histidine and arginine were resolved with acylase I; lysine was converted into its α,ϵ-dichloroacetyl derivative and resolved with acylase IA. The α-tritiated l-amino acids recovered from these reactions had the expected optical rotations. The specific activities of l-[α 3H]-histidine·HCl·H 2O, l-[α 3H]-arginine·HCl, and l-[α 3H]-lysine·HCl were 3.40 × 10 9, 4.47 × 10 9, and 1.03 × 10 9 dpm/mmole, respectively. l-[α 3H] Arginine·HCl was converted into l-ornithine·HCl and l-citrulline without change in specific activity. l-Arginine and l-citrulline, when subjected to the action of l-amino acid oxidase, gave α-keto-δ-guanidinovaleric and α-keto-δ-carbamidovaleric acids, which were devoid of any activity. ϵ-Cbzo- l-[α 3H]-lysine was prepared and subjected to the action of l-oxidase. The resulting α-keto-ϵ- N-Cbzo-aminocaproic acid had no activity. l-[α 3H]-histidine·HCl·H 2O was oxidized by nonenzymic means to imidazolelactic acid, cyanomethylimidazole, and imidazoleglyoxylic acid; the compounds retained 100, 8, and 2% of the original activity respectively. β-Imidazolyl-pyruvic acid could not be prepared by the action of venom l-amino acid oxidase. Imidazoleacetic acid prepared with this enzyme in the absence of catalase had 6% of the original l-histidine activity. It is concluded that tritium introduced into arginine and lysine by the azlactone rearrangement is exclusively linked to the α-carbon. For histidine, 92% of the label appeared in the α-position, 6% in the β-hydrogen atoms, and 2% in the imidazole ring. The difficulties in the determination of the tritium activity of histidine and its derivatives by liquid scintillation counting can be overcome by the addition of formaldehyde.

A hypnotic and possible analgesic effect of imidazoleacetic acid in mice

A hypnotic and possible analgesic effect of imidazoleacetic acid in mice

Inhibition of lysozyme by imidazole and indole derivatives

Imidazole, 4(5)-imidazole acetic acid, histidine, histidine methyl ester, and histamine, at varying concentrations, were found to inhibit the lysis by lysozyme of Micrococcus lysodeikticus cells or cell walls. From the pH profile of the extent of inhibition it is deduced that the enzyme is inhibited mainly by the protonated imidazole ring. Inhibition of lysozyme by imidazole or by the imidazole derivatives investigated was accompanied by a decrease in fluorescence intensity of the enzyme. Lysozyme activity could also be inhibited by 3-indole derivatives such as 3-indole propionic acid and tryptamine. The formation in aqueous solution of complexes of the charge-transfer type between compounds containing an indole ring and compounds containing a protonated imidazole ring has been demonstrated by a fluorescence quenching method, and by two thermodynamic methods. Compounds containing a protonated imidazole ring were shown to quench the fluorescence of indoles and to increase their solubilities in aqueous solution. From the temperature dependence of the association constants, enthalpies of association, ΛH, of about −3 Kcal per mole were calculated for the complexes indole-imidazole·HClO 4, 3-methyl indole-imidazole·HClO 4, indole-histidine·HClO 4, and 3-methyl indole-histidine·HClO 4. In view of the results obtained with lysozyme and with the low molecular weight model systems, it is suggested that inhibition of lysozyme by compounds containing a protonated imidazole ring is at least partially due to the formation of a charge-transfer complex with the tryptophan residues of the enzyme.

Gas chromatographic analysis of histamine metabolites in urine : Excretion Of Labelled Material in Dogs

Gas chromatographic analysis of urine has demonstrated that 1-methylimidazole-4-acetic acid as well as 1-methylimidazole-5-acetic acid is excreted by dogs. Subcutaneously administered labelled histamine in microgram quantities is excreted as 1-methylimidazole-4-acetic acid and imidazoleacetic acid, but does not contribute to the urine content of 1-methylimidazole-5-acetic acid. Histamine or histidien absorbed from the intestine do not seem to contribute to the next 24 hours' excretion of 1-methylimidazole-5-acetic or 1-methylimidazole-4-acetic acid.

Liberation of histamine in man. Gas chromatography of ring methylated imidazoleacetic acids in urine.

Liberation of histamine in man. Gas chromatography of ring methylated imidazoleacetic acids in urine.

Gas chromatographic analysis of histamine metabolites in urine : Quantitative determination of ring methylated imidazole-acetic acids in healthy man

A gas chromatographic method for the identification of 1-methylimidazole-4-acetic acid and 1-methylimidazole-5-acetic acid in urine, previously described, has been modified to allow the quantitative estimation of the 24 h excretion of the acids by man. The mean excretion of the two acids by healthy individuals was determined. The excretion of 1-methylimidazole-4-acetic acid, expressed in terms of creatinine ratios, varied within a rather narrow range (1.0–2.8 μg/mg of creatinine). It seems very likely that the estimation of this acid will give valuable information regarding the endogenous liberation and production of histamine. The daily excretion of the isomer, 1-methylimidazole-5-acetic acid was found to be very variable. The metabolic origin of this compound is discussed.

Gas chromatographic analysis of histamine metabolites in human urine : Ring methylated imidazoleacetic acids

The gas chromatographic properties of imidazoleacetic acid, of i-methylimidazole-4-acetic acid and of i-methylimidazole-5-acetic acid have been investigated, using different types of stationary phases. The above-mentioned imidazoleacetic acids have been isolated from normal human urine by an anion-exchange column. After esterification with HCl—methanol and extraction with chloroform, i-methylimidazole-4-acetic acid and i-methylimidazole-5-acetic acid have been separated by gas chromatography. The identity of the compounds was further established by mas spectrometric analysis of the gas chromatographic effluent. i-methylimidazole-4-acetic acid has previously been identified as a major excretory product of exogenously administered histamine. It has now been identified as a normal urinary constituent of man, as well as the isomeric i-methylimidazole-5-acetic acid. The metabolic origin of the latter compound is not known.

PRESENCE OF IMIDAZOLEACETIC ACID RIBOSIDE AND RIBOTIDE IN RAT TISSUES.

THE products of histamine metabolism in vivo have been catalogued in investigations of the urine1,2, but relatively little work has been done on metabolites present in tissues. Since excreted metabolites reflect only the composite outflow of terminal products and need not represent the metabolites present in a tissue, it seemed of interest to examine the radioactive compounds present in some tissues after the injection of labelled histamine and histidine. A special effort was made to demonstrate the presence of histamine adenine dinucleotide (HAD) and histamine adenine dinucleotide phosphate (HADP)3,4.

Distribution and Properties of Anaphylactic and Venom-Induced Slow-Reacting-Substance and Histamine in Guinea Pigs

Summary A striking parallel between the capacity of specific antigen and cobra venom to give rise to slow-reacting-substance activity in tissues of sensitized guinea pigs was demonstrated. By either method of treatment lung was the major source of slow-reacting-substance. Aorta, ileum, spleen and uterus showed considerably less capacity to form slow-reacting-substance. Antigen and venom showed significant differences in their ability to cause histamine release from various tissues. Both materials caused histamine release from lung, but venom produced considerably more histamine release than antigen from heart, kidney and diaphragm. Of several tissue lipid extracts examined, only lung lipid extract produced SRS on treatment with venom. Typical SRS activity was found to be present in untreated lipid extracts of brain and small intestine. Histamine was found in lipid extracts of lung and was dialyzable. Anaphylactic SRS was not dialyzable until it had been extracted into 80% ethanol in water. SRS formed from chopped lung treated with venom, however, was found to be dialyzable without extraction into ethanol. On the other hand, SRS prepared from lung lipid extract treated with venom was not dialyzable before or after ethanol extraction. The distribution of ethanol extracted anaphylactic SRS between ether and water at different pH values showed that it was not completely extractable into ether even at pH 2 to 3. Gasliquid chromatography of anaphylactic SRS preparations following methanolysis did not show a pattern of fatty acids different from control samples. On the basis of these observations anaphylactic SRS does not appear to be a fatty acid. Four metabolites of histamine, N-acetylhistamine, imidazole-acetic acid, methylhistamine and methylimidazole-acetic acid, as well as histamine incubated with venom, failed to show SRS activity.

Studies on xanthine oxidaseI. Activation of milk xanthine oxidase by histamine

1. Histamine counteracts the inhibitory action of excess hypoxanthine or xanthine on xanthine oxidase (xanthine: O2 oxidoreductase, EC 1.2.3.2), but has no effect at low concentrations o substrate. 2. The effect of histamine is more definite at alkaline pH, with decreasing concentration of enzyme, and with increasing duration of incubation. 3. The activity of xanthine oxidase with, or without, histamine is largely influenced by the kind of buffer. The maximum effect of histamine is obtained with dilute solution of potassium phosphate buffer. 4. The effect of histamine is observed practically on all the samples of the enzyme prepared by Ball's method, although its extent varies from batch to batch. Purification of the enzyme raises the rate of activation. Trypsin treatment of the enzyme has no influence on the appearance of the “histamine effect”. 5. An effect similar to that of histamine is produced by l-histidine, KCN and EDTA. A less-marked effect is produced by imidazoleacetic acid, riboflavin, 5-hydroxytryptamine, l-arginine, l-lysine and glycine. 6. It is suggested that histamine may remove metallic ion(s) which are toxic to the enzyme.

Studies on xanthine oxidase

Abstract 1. 1. Histamine counteracts the inhibitory action of excess hypoxanthine or xanthine on xanthine oxidase (xanthine: O2 oxidoreductase, EC 1.2.3.2), but has no effect at low concentrations o substrate. 2. 2. The effect of histamine is more definite at alkaline pH, with decreasing concentration of enzyme, and with increasing duration of incubation. 3. 3. The activity of xanthine oxidase with, or without, histamine is largely influenced by the kind of buffer. The maximum effect of histamine is obtained with dilute solution of potassium phosphate buffer. 4. 4. The effect of histamine is observed practically on all the samples of the enzyme prepared by Ball's method, although its extent varies from batch to batch. Purification of the enzyme raises the rate of activation. Trypsin treatment of the enzyme has no influence on the appearance of the “histamine effect”. 5. 5. An effect similar to that of histamine is produced by l -histidine, KCN and EDTA. A less-marked effect is produced by imidazoleacetic acid, riboflavin, 5-hydroxytryptamine, l -arginine, l -lysine and glycine. 6. 6. It is suggested that histamine may remove metallic ion(s) which are toxic to the enzyme.

Biochemistry of uric acid and its relation to gout.

Interrelation of Carbohydrate and Urate Metabolism Purine metabolism is related both directly and indirectly to carbohydrate metabolism. A direct relation is found in the origin of the ribose moiety of the purine nucleotide from glucose by way of the ribose compound, phosphoribosylpyrophosphate (PRPP) (Fig. 4). Gouty subjects who produce excessive quantities of uric acid also show an increased incorporation of glucose-C14 into the ribose-containing urinary excretion product imidazoleacetic acid riboside, which also arises from PRPP. This increased formation of PRPP from glucose, however, is regarded as showing increased turnover of PRPP in association with an increased purine biosynthesis rather than . . .

On the response of the stretch receptor neurones of crayfish to 3-hydroxytyramine and other compounds

1. 1. The inhibitory activities of γ-aminobutyric acid, 3-hydroxytyramine, imidazoleacetic acid and homotaurine upon the slowly adapting neurones of four species of crayfish have been compared. 2. 2. 3-Hydroxytyramine is active only on Pacifastacus leniusculus and Procambarus clarkii and is without effect on Orconectes propinquus and Procambarus blandingi. 3. 3. The other three compounds are approximately equally active on all four species. Homotaurine has here been tested for the first time and has been found to have about 1·3 times the potency of γ-aminobutyric acid. 4. 4. These results may serve to explain the failure of other workers to detect an inhibitory effect of 3-hydroxytyramine upon crayfish stretch receptor neurons.

Histidinemia: A deficiency in histidase resulting in the urinary excretion of histidine and of imidazolepyruvic acid

Summary A case of histidinemia is described in which the biochemical abnormality can be attributed to a deficiency of the enzyme histidase. As a result of this deficiency, plasma and urinary levels of histidine are markedly elevated. Imidazolepyruvic, imidazolelactic, and imidazoleacetic acids are excreted in the urine in excessive amounts. The presence of imidazolepyruvic acid in the urine is responsible for a positive test with ferric chloride similar to that due to phenylpyruvic acid found in the urine of patients with phenylketonuria. The possibility of a deficiency of urocanase was ruled out by the demonstration of considerable amounts of formiminoglutamic acid in the urine of the patient following administration of urocanic acid.

Imidazolytic processes V. Enzymically-catalyzed reactivity of certain imidazoles with coenzyme I

In the DPN-DPNase system that catalyzes the (imidazolytic) breakdown of pyridine coenzymes, l-histidine and imidazoleacetic acid were found practically unreactive. The reactivity of the latter compound could be restored by esterification to imidazoleacetic acid ethylester. Imidazole, the parent compound of these heterocycles, and acetylhistamine exhibited normal reactivity. The dinucleotides (imidazolytic products) corresponding to the above compounds were isolated and their properties were studied.

Protection by histamine and metabolites in anaphylaxis, scalds, and endotoxin shock.

The release of toxic factors has been implicated in the mechanism of shock from various forms of trauma. If histamine (H) released after anaphylaxis, endotoxin shock, or thermal burns is a lethal factor in mice, priming with (H) before injury would presumably enhance mortality. Mice were pretreated with (H) or certain metabolites prior to inducing shock via horse serum anaphylaxis, scald injury, or lethal dose of E. coli endotoxin. Large doses of (H) did not enhance mortality; actually, mortality from these three forms of shock was lowered by pretreatment with (H) or imidazoleacetic acid, but not by other metabolites tested. The data, while unexplained, do not appear to support hypotheses assigning an active role to (H) release in these three forms of shock in mice.