There is a strong association between histamine level and age; as age increase the histamine level decrease. Also between sun sensitivity and histamine level there is a strong association. The lower the histamine level the higher the percentage of sun sensitivity patients. This suggests there should be a metabolic explanation for the association between histamine level, sun sensitivity and age. In this report we try to give a explanation for sun sensitivity in HPU-patients.
Looking at the results over the past ten years, the one association that is striking, is the inverse relationship between histamine level and age. This is not a new finding. But within the group of HPU-patients it is clear from the present study that this relationship is much stronger in a statistical sense than in open population.
Looking at a sub-group of controls, almost all of the people with very low histamine levels had poor folic acid status. Even where this did not show as a low red-cell folate, there was an increase in FIGLU-excretion (Formiminoglutamic acid) after histidine loading. When the really low folate controls are removed from the forementioned statistics, the relationship between histamine and age strengthens to a very high statistical significance.
Further investigation according to Howard MacLaren Howard (pers. comm.), although it is so far that the complete research has been carried out on a relatively small group, shows that extreme low histamine level and FIGLU excretion correlates very well for around 85% of the patients. In general, as FIGLU increases (reflecting poor folate status) histamine decreases.
It is very clear from the findings that the poor folate status is not be the only reason for low histamine levels. FIGLU excretion after amino acid loading, being the most reliable predictor of folate deficiency and low histamine is only true for young female patients with very low hitamine levels. However, the relationship between the age of the patient, poor folate status and lowered histamine is statistically of very high significance. On the other hand high copper levels tends to decrease the histamine levels too. Copper tends to activate MAO and DAO enzymes that will break down histamine. This shows to be the other main reason for low histamine levels in HPU-patients. This is not influenced by using a copper containing birth control device.
Histamine is formed from histidine by histidine decarboxylase. All decarboxylation reactions are pyridixal-5-phosphate dependent. Because of the deficiency of pyridoxal-5-phosphate in HPU-patients histidine is not converted to histamine but the concentration of histidine is increased. This histidase is both induced by high histidine levels, hormones like estrogens and other porfyrinogens. Histidine will be converted, as age increases, very rapidly in urocanic acid.
The pathway of FIGLU-formation
If histidine is not converted to histamine by decarboxylase, histidine will converted to FIGLU and if there is no folate deficiency into glutamic acid and formyl-THFA. The first reaction in this pathway is the nonoxidative deamination of L-histidine to trans-urocanic acid by histidase (histidine ammonia-lyase). In this reaction ammonia is released.1,2 This enzyme is expressed with high activity in the liver and in the skin.3,4 Histidase is regulated in a complex developmental, hormonal, and tissue-specific manner.5-8
In contrast, hepatic activity is not detectable until four days after birth, and subsequently increases gradually until puberty. Adult females have a twofold higher level of hepatic histidase than males, owing to estrogen induction.5-7 Other hormones, including glucocorticoids, glucagon, and triiodothyronine, also regulate hepatic histidase, albeit to a lesser extent than estrogen.5,6,8 Dietary regulation of hepatic histidase has been demonstrated. High-protein diet show increased hepatic histidase activity.9,10
However, the differences between the developmental programs of histidase in liver and epidermis could reflect differences in the metabolism of urocanic acid in these two tissues. In the liver, urocanic acid is an intermediate in the conversion of histidine to glutamic acid, whereas in the epidermis, it accumulates and may be both a UV protectant and an immunoregulator.
Urocanase catalyses the nonoxidative conversion of trans-urocanic acid to imidazolonepropionic acid. Imidazolonepropionic Acid Hydrolase converts imidazolonepropionic acid to formiminoglutamic acid (FIGLU), an important intermediate that links histidine catabolism to folate metabolism. FIGLU is a donor of formyl groups to tetrahydrofolic acid and is a marker for folic acid deficiency.11
Formiminotransferase catalyses the formation of formiminotetrahydrofolic acid from FIGLU. Tetrahydrofolic acid is required for this reaction, and glutamic acid is liberated. Folic acid deficiency results in a strikingly increased excretion of FIGLU in response to loading with L-histidine, presumably due to the reduction in available tetrahydrofolic acid.12 Trans-urocanic acid is formed from the deamination of L-histidine by histidase in the liver and in the stratum corneum.13 In the epidermis, trans-urocanic acid (lmax = 275 nm) undergoes an isomerization to cis-urocanic acid in UV light,14 the proportion of cis and trans isomers varying according to the UV light exposure.15,16
Epidermal urocanic acid probably acts as natural sunscreen17,18 led to the hypothesis that the deficiency of urocanic acid in the skin causes more sensitivity to sunlight and more susceptible to sunburn than others. The ability of urocanic acid to protect skin from sunburn has been demonstrated by a number of investigators.19-23 A study of skin erythema in histidinemic children suggested increased sensitivity to UV light.24 Urocanic acid in the skin may also reduce photomutagenesis, since the absorption spectra of both the cis and trans isomers of urocanate overlap with the absorption spectrum of DNA.14
In HPU-patients the histamine level is not only decreased because of the deficiency of folic acid by also by the induction of the enzyme activity of MAO and DAO enzymes by copper. Even more than in open population the association between age and histamine level is very strong. But even at very young age (18-25 years) some women with HPU shoes markedly decreased histamine levels. In almost al these patients a certain amount of sun sensitivity excists.
In HPU-patients which strongly decreased histamine levels, histidase activity is strongly increased. This probably shows an induction mechanism on liver histidase. This is not only caused by estrogen in birth control pills, but also by porfyrinogenic substances with cannot be excreted by HPU-patients.Birth control pills are used on very young age (from 13 years and older) because of the severe menstrual problems which starts because of the deficiency of pyridoxaal-5-phosphate. Estrogen happens to be one of the main porfyrinogens in these young girls. Histadine levels are in fact low in plasma and urine of HPU-patients. HPU-patient are sun sensitive as well. In the questionnaires of HPU-patients there was a striking association between sun sensitivity and low histamine levels. Probably there is hardly enough histidine in the epidermis to be converted by the epidermal-histidase in the skin in trans-urocanic acid. That’s why the UV-screen is hardly build up and probably sun sensitivity develops.
- Peterkofsky A: The mechanism of action of histidase: Amino-enzyme formation and partial reactions. J Biol Chem 237:787, 1962.
- Furuta T, Takahashi H, Shibasaki H, Kasuya Y: Reversible stepwise mechanism involving a carbanion intermediate in the elimination of ammonia from L-histidine catalyzed by histidine ammonia-lyase. J Biol Chem 267:12600, 1992.
- Dhanam M, Radhakrishnan AN: Comparative studies on histidase: Distribution in tissues, properties of liver histidase and its development in rat. Indian J Exp Biol 14:103, 1976.
- Bhargava MM, Feigelson M: Studies on the mechanisms of histidase development in rat skin and liver. I. Basis for tissue specific developmental changes in catalytic activity. Dev Biol 48:212, 1976.
- Feigelson M: Multihormonal regulation of hepatic histidase during postnatal development. Enzyme 15:169, 1973.
- Lamartiniere CA, Feigelson M: Effects of estrogen, glucocorticoid, glucagon, and adenosine 3´:5´-monophosphate on catalytic activity, amount, and rate of de novo synthesis of hepatic histidase. J Biol Chem 252:3234, 1977.
- Lamartiniere CA: Neonatal estrogen treatment alters sexual differentiation of hepatic histidase. Endocrinology 105:1031, 1979.
- Armstrong EG, Feigelson M: Effects of hypophysectomy and triiodothyronine on de novo biosynthesis, catalytic activity, and estrogen induction of rat liver histidase. J Biol Chem 255:7199, 1980.
- Kang-Lee YAE, Harper AE: Effect of histidine intake and hepatic histidase activity on the metabolism of histidine in vivo. J Nutr 107:1427, 1977.
- Cedrangolo F, Illiano G, Servillo L, Spina AM: Histidine degradation enzymes in rat liver: Induction by high protein intake. Mol Cell Biochem 23:123, 1979.
- Rao DR, Greenberg DM: Studies on the enzymic decomposition of urocanic acid. IV. Purification and properties of 4(5)imidazolone-5(4)propionic acid hydrolase. J Biol Chem 236:1758, 1961.
- Luhby AL, Cooperman JM, Teller DN: Histidine metabolic loading test to distinguish folic acid deficiency from vit. B12 in megaloblastic anemias. Proc Soc Exp Biol Med 101:350, 1959.
- Scott IR: Factors controlling the expressed activity of histidine ammonia-lyase in the epidermis and the resulting accumulation of urocanic acid. Biochem J 194:829, 1981.
- Morrison H, Avnir D, Bernasconi C, Fagan G: Z/E photoisomerization of urocanic acid. Photochem Photobiol 32:711, 1980.
- Norval M. Simpson TJ, Bardshiri E, Crosby J: Quantification of urocanic acid isomers in human stratum corneum. Photodermatology 6:142, 1989.
- Pasanen P, Reunala T, Jansen Jansén CT, Rasanen Räsänen L, Neuvonen K, Ayras P: Urocanic acid isomers in epidermal samples and suction blister fluid of non-irradiated and UVB-irradiated human skin. Photodermatology 7:40, 1990.
- Zenisek A, Kral JA The occurrence of urocanic acid in human sweat. Biochim Biophys Acta 12:479, 1953.
- Zenisek A, Kral JA, Hais IM: “Sun-screening” effect of urocanic acid. Biochim Biophys Acta 18:589, 1955.
- Everett MA, Anglin JH Jr, Bever AT: Ultraviolet induced biochemical alterations in skin. I. Urocanic acid. Arch Dermatol 84:717, 1961.
- Baden HP, Pathak MA: The metabolism and function of urocanic acid in skin. J Invest Dermatol 48:11, 1967.
- Zenisek A, Hais IM, Strych A, Kral JA: Does solar irradiation affect the natural antisunburn properties of the skin? Fr Ses Parfums 12:131, 1969.
- Wadia AS, Sule SM, Mathur GP: Epidermal urocanic acid and histidase of albino guineapig following total body UV-irradiation. Indian J Exp Biol 13:234, 1975.
- Ohnishi S, Nishijima Y, Hasegawa I, Futagoishi H: Study of urocanic acid in the human skin surface (II). Geometrical isomers and sunscreen effect. J Soc Cosmet Chem Jpn 13:61, 1979.
- Baden HP, Hori Y, Pathak MA and Levy HL: Epidermis in histadinemia. Arch. Dermatol 100:432. 1969