Disease relevance of urocanic acid

• Here, Frances Noonan and Edward De Fabo assess the evidence that suppression is initiated by the photoisomerization of trans-urocanic acid (UCA) in the stratum corneum, discuss the significance of this mechanism for skin cancer outgrowth and propose applications for UCA in transplantation [1].
• Differential effects of a monoclonal antibody to cis-urocanic acid on the suppression of delayed and contact hypersensitivity following ultraviolet irradiation [2].
• Thus, there appeared to be a correlation between protection from edema and from cis urocanic acid formation at 3 x MED of UVB, but a dissociation of these variables at 15 x MED of UVB [3].
• UVA exposure affects UVB and cis-urocanic acid-induced systemic suppression of immune responses in Listeria monocytogenes-infected Balb/c mice [4].
• Epidermal cis-urocanic acid levels correlate with lower specific cellular immune responses after hepatitis B vaccination of ultraviolet B-exposed humans [5].

High impact information on urocanic acid

• In this Account, we describe recent research efforts directed at elucidating the UV-A-induced photoreactivity of two light-absorbing epidermal photoreceptors: trans-urocanic acid and eumelanin [6].
• However, such exposure to UVA radiation has been observed unexpectedly to induce resistance to UVB-induced immunosuppression in mice, by a mechanism resulting in the inactivation of cis-urocanic acid (UCA), an epidermal immunosuppressive UV photoproduct [7].
• The data presented provide evidence suggesting that the UV-A excitation of trans-urocanic acid initiates chemical processes that result in the photoaging of skin [8].
• IL-12 prevents the inhibitory effects of cis-urocanic acid on tumor antigen presentation by Langerhans cells: implications for photocarcinogenesis [9].
• In this study, cis-urocanic acid suppressed human monocyte production of TNF-alpha by a PGE2-dependent mechanism [10].

Chemical compound and disease context of urocanic acid

• Pyridoxine supplementation protects mice from suppression of contact hypersensitivity induced by 2-acetyl-4-tetrahydroxybutylimidazole (THI), ultraviolet B radiation (280-320 nm), or cis-urocanic acid [11].
• Histamine involvement in UVB- and cis-urocanic acid-induced systemic suppression of contact hypersensitivity responses [12].
• Mice fed a diet containing 1% aged garlic extract were partially protected from cis-urocanic acid-induced suppression of contact hypersensitivity, with greater protection from the lower concentrations of urocanic acid [13].
• Carnosine (beta-alanylhistidine) protects from the suppression of contact hypersensitivity by ultraviolet B (280-320 nm) radiation or by cis urocanic acid [14].
• Tumour necrosis factor-alpha (TNF-alpha) and cis-urocanic acid (UCA) have recently been implicated in the process by which ultraviolet B radiation (UVB) impairs the induction of contact hypersensitivity when dinitrofluorobenzene (DNFB) is painted on UVB-exposed skin [15].

Biological context of urocanic acid

• Evidence exists implicating the epidermal ultraviolet B (UVB) photoproduct cis-urocanic acid as an immunogenic mediator of the systemic suppression of T cell-mediated immunity by UVB exposure [11].
• These results suggest that pyridoxine competes with cis-urocanic acid and THI for the same binding site or receptor, which we postulate to be a histamine-like T lymphocyte receptor, and that a role may exist for the control of photoimmunosuppression by this vitamin [11].
• These results demonstrate that PUVA treatment or its chemical mediator, cis-urocanic acid, may be used in transplantation and hematology as naturally occurring immunosuppressive agents, especially for the control and manipulation of GVH leukemia reaction [16].
• However, contact hypersensitivity can also be suppressed in the opossum with exogenous cis-urocanic acid, a molecule which is produced in UVB-irradiated epidermis and is a second potential mediator of photo-immunosuppression apparently independent of UVB-induced DNA damage [17].
• Under the conditions of refractory HO enzyme induction, the protective effect of UVA radiation against the suppression of contact hypersensitivity induced by UVB radiation or cis-urocanic acid was strongly attenuated but was restored when the interval between UVA exposures was increased to 96 h [18].

Anatomical context of urocanic acid

• In the absence of a direct stimulatory effect of cis-urocanic acid on connective tissue mast cells, an indirect association was investigated [19].
• Histamine and cis-urocanic acid augment tumor necrosis factor-alpha mediated induction of keratinocyte intercellular adhesion molecule-1 expression [20].
• Cis-urocanic acid, a product formed by ultraviolet B irradiation of the skin, initiates an antigen presentation defect in splenic dendritic cells in vivo [21].
• A monoclonal antibody to cis-urocanic acid prevents the ultraviolet-induced changes in Langerhans cells and delayed hypersensitivity responses in mice, although not preventing dendritic cell accumulation in lymph nodes draining the site of irradiation and contact hypersensitivity responses [22].
• The humoral immune response to sheep erythrocytes is not influenced by cis-urocanic acid [16].

Associations of urocanic acid with other chemical compounds

• It was then found that: (i) pK of these proton donors (pK = 6.13 +/- 0.07) was quasi-identical to that of trans-urocanic acid (6.10), and (ii) the amount of urocanic acid present in stratum corneum was sufficient in itself to explain the acidic level as measured with pH meter (R = 0.8484, n = 10, p = 0.00136) [23].
• In mice bearing a null mutation for MT-I and -II, we found that immunoprotection by the isoflavonoid 4',7-dihydroxyisoflavane (equol) against solar-simulated UV radiation (SSUV) or exogenous cis-urocanic acid was abrogated [24].
• A blister induced in the rat hind footpad was used to examine the effects of slowly perfused cis-urocanic acid on cutaneous blood flow. cis-Urocanic acid but not trans-urocanic acid increased microvascular flow by a mechanism largely dependent on the combined activity of the neuropeptides, substance P and calcitonin gene-related peptide [19].
• N-acetylcysteine proved not to have any effect on the photoisomerization of trans-urocanic acid (UCA) to its cis-form in vitro; at equilibrium, approximately 55% cis-UCA was formed [25].
• One initiator of this complex process is cis-urocanic acid (cis-UCA), which is formed from the naturally occurring trans isomer in the epidermis on absorption of UV. cis-UCA has been shown to have immunomodulating properties in a variety of in vivo and in vitro experimental systems, although its mechanism of action is not yet clear [26].

Gene context of urocanic acid

• In response to ultraviolet B irradiation or topical cis-urocanic acid treatment, control mice became immunosuppressed by 69% and 27%, respectively, and interferon-gamma-/- mice by 79% and 27% [27].
• The mechanism of this immunomodulation is unclear but various regulatory molecules have been implicated, including cis-urocanic acid (cis-UCA) and the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin 10 (IL-10) [28].
• cis-urocanic acid suppression of contact hypersensitivity induction is mediated via tumor necrosis factor-alpha [29].
• We have investigated the riboflavin (RF)-sensitized inactivation of glucose 6-phosphate dehydrogenase (G6PD) in the presence and absence of trans-urocanic acid (UCA) [30].
• In addition to a role for UCA and DNA in UV-induced immunosuppression it is postulated recently that signal transduction (EGF-receptor mediated upregulation of phospholipase A2) and transcription factors (NF kappa B, p91) are involved in UV-induced immunomodulation [31].

Analytical, diagnostic and therapeutic context of urocanic acid

• Photoisomerization of trans-urocanic acid (UCA) in the stratum corneum has been implicated in the immunosuppression detected after irradiation with UVB (UV wavelength of 280-320 nm) [10].
• Unirradiated (trans-urocanic acid) had no effect on allograft rejection [32].
• Perfusion of cis-urocanic acid over the base of blisters induced in sensory-neuropeptide-depleted rats did not have any stimulatory effect above that seen with perfusion of cis-urocanic acid together with neuropeptide receptor antagonists in control rats [19].
• Irradiation-induced isomerisation of trans-urocanic to cis-urocanic acid was quantitated by UV spectroscopy after separation of the isomers by high performance liquid chromatography [33].
• Differential suppression of the human mixed epidermal cell lymphocyte reaction (MECLR) and mixed lymphocyte reaction (MLR) by cis-urocanic acid [34].

References