- GABA_A receptor: Both Urocanic acid isomers bind to GABA_A receptors on rat cortex membranes. cis-UCA displaced [H]-GABA by 48%, and trans-UCA by 19% at pH 5.5 (the pH of skin). The isomers were more potent at pH 5.5 than at pH 7.4. cis-UCA inhibited GABA responses, while trans-UCA slightly enhanced them. [1]
- Serotonin (5-HT2A) receptor: cis-Urocanic acid binds to the 5-HT2A receptor with relatively high affinity, while trans-UCA does not. Treatment with a selective serotonin antagonist blocked the binding of cis-UCA, and 5-HT acted as a competitive inhibitor for the binding of cis-UCA. cis-UCA mobilized intracellular calcium stores within cells expressing serotonin receptors. [1]

Urocanic acid (UCA) is created in the epidermis' upper layers when filaggrin, a histidine-rich filamentous protein synthesized following profilaggrin cleavage by caspase-14, is broken down by proteinases into component amino acids[1].

---

- In primary human keratinocytes, cis-Urocanic acid induced the production of several cytokine proteins, including TNF-α. Prostaglandin-endoperoxide synthase 2 was highly up-regulated by cis-UCA, resulting in enhanced secretion of prostaglandin E2 into the culture supernatant. [1]
- cis-Urocanic acid acted in synergy with histamine to induce the production of prostaglandin E2 from human keratinocytes in vitro. [1]
- In mouse spleen cell cultures, cis-Urocanic acid suppressed antigen presentation by stimulating IL-10 production by activated CD4+ T cells. The main target was the CD4+ T cell population, not macrophages or other cell types. [1]
- cis-Urocanic acid did not change the development of dendritic cells derived from bone marrow or their allo-antigen presenting capability. It also did not alter the expression of MHC Class II or co-stimulatory molecules required for effective antigen presentation. [1]
- In a mouse tumour model, when epidermal cells (containing 5-15% Langerhans cells) were incubated ex vivo with a tumour-associated antigen in the presence of cis-Urocanic acid, the protective effect (tumour rejection upon subsequent challenge) was lost, indicating that cis-UCA down-regulated the ability of epidermal cells to present the tumour antigen. This suppression was prevented by adding IL-12 to the incubation. cis-UCA acted mainly by impairing antigen processing. [1]
- In human neutrophil studies, cis-Urocanic acid suppressed the generation of extracellular superoxide (respiratory burst activity) while not affecting the generation of intracellular superoxide or other reactive oxygen species. Phagocytic and bactericidal activities were not altered by cis-UCA. [1]
- In a human skin organ culture, cis-Urocanic acid induced mast cell degranulation, depleting mast cell chymase and producing TNF-α. [1]
- In rat cortex membranes, both Urocanic acid isomers bound to GABA_A receptors. cis-UCA displaced [H]-GABA by 48% and trans-UCA by 19% at pH 5.5. cis-UCA inhibited GABA responses, while trans-UCA slightly enhanced them. [1]
- In cells expressing serotonin receptors, cis-Urocanic acid mobilized intracellular calcium stores, indicating engagement of the serotonin receptor. [1]

- In mice, topical application of Urocanic acid (unspecified isomer, but likely cis or mixture) increased both the incidence and malignancy of UVR-induced skin cancers. [1]
- In mice treated with an anti-cis-Urocanic acid antibody intraperitoneally before each UVB exposure over 6 months, only 50% of animals developed skin tumours after 200 days, whereas all animals in control groups developed tumours after 182 days. [1]
- In a rat model of Trichinella spiralis infection, subcutaneous injection of cis-Urocanic acid (dose range not specified) increased the number of larvae in muscle tissue and significantly suppressed the delayed-type hypersensitivity (DTH) response to T. spiralis antigens. Injection of an anti-cis-UCA antibody before UV irradiation abrogated these effects. [1]
- In a hairless guinea-pig model of Buruli ulcer (Mycobacterium ulcerans infection), topical treatment for 3 consecutive days with a 1:9 cis:trans-Urocanic acid mixture resulted in more severe skin lesions and suppressed DTH responses compared to trans-UCA or vehicle controls. [1]
- In human volunteers exposed to 1 personal minimal erythema dose (MED) of UVB on 5 consecutive days then vaccinated with hepatitis B surface antigen, subjects with higher cis-Urocanic acid concentration after UV exposure had slightly lowered hepatitis B-specific lymphocyte responses. [1]
- In mice, topical application of cis-Urocanic acid suppressed contact hypersensitivity (CHS) responses. This effect was absent in mast cell-deficient mice, and susceptibility was restored by reconstituting dorsal skin with bone-marrow-derived mast cell precursors. [1]
- In rats, perfusion of a blister on the hind footpad with cis-Urocanic acid (but not trans-UCA) increased microvascular flow via neuropeptide release, specifically substance P and calcitonin gene-related peptide (CGRP). [1]
- In mice treated with capsaicin to deplete sensory neuropeptides, cis-Urocanic acid did not suppress CHS responses. [1]
- In mice, prior or concurrent exposure to UVA protected against immunosuppression caused by UVB or cis-Urocanic acid, mediated by heme oxygenase-1 (HO-1) induction and carbon monoxide production. [1]

GABA_A receptor binding assay: Rat cortex membranes were used to analyze binding of Urocanic acid isomers to histamine H1, H2, H3 receptors and GABA_A receptors. Competitive binding curves did not provide evidence for histamine receptors, but both isomers bound to GABA_A receptors. cis-UCA displaced [H]-GABA by 48% and trans-UCA by 19%. The isomers were more potent at pH 5.5 than at pH 7.4. [1]
- Serotonin receptor binding and functional assay: Cells expressing serotonin receptors were used. cis-Urocanic acid bound to the 5-HT2A receptor with relatively high affinity while trans-UCA did not. A selective serotonin antagonist blocked binding. 5-HT acted as a competitive inhibitor. cis-UCA mobilized intracellular calcium stores within these cells. [1]
- Reactive oxygen species generation assay: Human neutrophils were activated, and the respiratory burst activity was measured. cis-Urocanic acid suppressed the generation of extracellular superoxide but not intracellular superoxide or other ROS. [1]

- Mouse photocarcinogenesis study: Mice were irradiated with increasing doses of UVB over 6 months, then observed for skin tumour development for another 6 months. One group received intraperitoneal injections of anti-cis-Urocanic acid antibody before each UVB exposure. Control groups received no antibody or an irrelevant isotype-matched antibody. [1]
- Rat Trichinella spiralis infection model: Rats were infected orally with T. spiralis, then injected subcutaneously with a range of doses of cis- or trans-Urocanic acid. The number of larvae in muscle tissue and DTH response to T. spiralis antigens were assessed. Another group received anti-cis-UCA antibody before UV irradiation and infection. [1]
- Hairless guinea-pig Buruli ulcer model: Animals were treated topically for 3 consecutive days with trans-Urocanic acid, a 1:9 cis:trans-UCA mixture, or vehicle. They were then infected intradermally with Mycobacterium ulcerans. Skin lesions and DTH response to M. ulcerans antigens were measured. [1]
- Human volunteer UVB exposure and hepatitis B vaccination: Volunteers were exposed to 1 personal MED of UVB on 5 consecutive days, then vaccinated with hepatitis B surface antigen. Skin UCA isomer levels were measured before and after UV exposure. Lymphocyte responses to mitogens, recall antigens, and hepatitis B virus were measured at several time points. [1]
- Mouse contact hypersensitivity (CHS) study: Mice were treated with topical cis-Urocanic acid and assessed for CHS suppression. Mast cell-deficient mice and capsaicin-treated mice (to deplete sensory neuropeptides) were used. [1]
- Rat blister perfusion study: A blister was induced on the hind footpad of rats. After removal of the surface epithelium, the area was perfused with cis-Urocanic acid, trans-UCA, or other molecules. Microvascular flow and neuropeptide release (substance P, CGRP) were measured. [1]
- Mouse UVA protection study: Mice were pre-exposed to UVA before UVB irradiation or cis-Urocanic acid treatment, then infected with Listeria monocytogenes. Immune response was assessed. [1]

- In human skin, cis-Urocanic acid persists in the epidermis for at least 2 weeks following UV exposure, gradually returning to background level during that time. [1]
- cis-Urocanic acid is found for several weeks in suction blister fluid, indicating its presence in the dermis. [1]
- cis-Urocanic acid is detected in serum for 1-2 days after UVR. [1]
- cis-Urocanic acid is excreted in urine for about 2 weeks after UV exposure. [1]
- In human skin, total Urocanic acid concentration varies between individuals (more than 10-fold differences), with median approximately 20 nmol/cm². Concentration varies by body site (higher in buttock and arm, lower in forehead). In children, unexposed site (buttock) median 22.2 nmol/cm²; sun-exposed site (upper back) cis-UCA percentage median 60.1% vs. 28.3% in adults. Seasonal variation: cis-UCA levels in summer close to maximum at all body sites except buttock; in winter, cis-UCA fell below 7% except forehead (18%). [1]
- In hairless mice, total Urocanic acid concentration is approximately 5 nmol/cm². [1]
- In marsupial opossum Monodelphis domestica, Urocanic acid concentration about 12 nmol/cm²; in some Australian marsupials about 120 nmol/cm², mostly in dermis. [1]

- A single administration of cis-Urocanic acid led to decreased splenocyte phagocytosis in C57BL/6N mice. [1]
- Prolonged cis-Urocanic acid treatment (4 weeks) resulted in thymic atrophy and hypocellularity, and in splenic and lymph node hypercellularity in both C57BL/6N and C3H/HeN strains of mice. [1]
- In human skin, Urocanic acid concentration does not correlate with photosensitivity or minimal erythema dose (MED). [1]

[1]. Recent advances in urocanic acid photochemistry, photobiology and photoimmunology. Photochem Photobiol Sci. 2008 Jun;7(6):655-67.

Urocanic acid is an α,β-unsaturated monocarboxylic acid formed by the substitution of a 2-enoic acid at the 3-position with a 1H-imidazol-4-yl group. It is a metabolite of uridine. It is both a chromophore and a human metabolite. It is an α,β-unsaturated monocarboxylic acid belonging to the imidazole class of compounds. It is the conjugate acid of Urocanic acid. Urocanic acid is a metabolite found or produced in Escherichia coli (K12 strain, MG1655 strain). It has been reported to exist in Homo sapiens, common sponges, and other organisms with relevant data. 4-Imidazole acrylic acid.

---

- Urocanic acid is synthesised from histidine via deamination in the skin. Total UCA concentration correlates with dietary L-histidine levels. [1]
- The photoisomerisation of trans- to cis-Urocanic acid is wavelength-dependent with peak efficiency (Φ=0.49) at 310 nm and lower efficiency (Φ=0.05) at the trans-UCA absorption maximum of 268 nm. The action spectrum for cis-UCA production in skin is red-shifted (280-310 nm). [1]
- The trans-Urocanic acid triplet state has a triplet energy of about 230 kJ mol⁻¹ and lifetime of approximately 10⁻⁷ s⁻¹, capable of energy transfer to molecular oxygen to form singlet oxygen (¹O₂) in the UVA region (315-380 nm) with peak efficiency at 340 nm. [1]
- Urocanic acid acts as a hydroxyl radical scavenger but an inefficient peroxyl radical scavenger. UVB exposure produces oxidation products (Imidazole-4-carboxaldehyde, Imidazole-4-carboxylic acid, Imidazole-4-acetic acid, Glyoxylic acid) which also possess immunosuppressive properties comparable to cis-UCA. [1]
- In humans, Urocanic acid levels in skin do not differ between patients with a past history of basal cell carcinoma (BCC), cutaneous malignant melanoma (CMM), or nonmelanoma skin cancer (NMSC) and healthy controls, nor does the rate of photoisomerisation. [1]
- cis-Urocanic acid is involved in UV-induced skin cancer in mice, acting at an early stage of carcinogenesis rather than later progression. [1]
- Urocanic acid is a major chemoattractant for the skin-penetrating nematode Strongyloides stercoralis (likely trans-UCA). [1]
- Protective strategies against cis-Urocanic acid-induced immunosuppression include: omega-3 fatty acid (eicosapentaenoic acid, EPA), Pycnogenol (antioxidant from pine bark), isoflavonoids (e.g., equol from red clover), and UVA pre-exposure (via heme oxygenase-1 and carbon monoxide pathway). [1]

C6H6N2O2

138.1240

138.042

104-98-3

736715

White to off-white solid powder

1.4±0.1 g/cm3

456.9±20.0 °C at 760 mmHg

225 °C

230.1±21.8 °C

0.0±1.2 mmHg at 25°C

1.674

0.01

2

3

2

10

156

0

C1=C(NC=N1)/C=C/C(=O)O

LOIYMIARKYCTBW-OWOJBTEDSA-N

InChI=1S/C6H6N2O2/c9-6(10)2-1-5-3-7-4-8-5/h1-4H,(H,7,8)(H,9,10)/b2-1+

(E)-3-(1H-imidazol-5-yl)prop-2-enoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~362.00 mM)
H2O : ~2 mg/mL (~14.48 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (15.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.08 mg/mL (15.06 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (15.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 2 mg/mL (14.48 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

---

 (Please use freshly prepared in vivo formulations for optimal results.)