Relations of a New Metabolic Pathway and Immunosuppressive Effects of Urocanic Acid to its Isomerization by Exposure of Skin to Ultraviolet Light

在皮肤中，由于皮肤中没有尿酸水合酶，L-组氨酸在组氨酸解氨酶作用下只形成反式尿藻酸，然后积累在表皮中。表皮尿囊酸在紫外光作用下异构化为顺式异构体。然而，这种积累和异构化的生理功能还没有被阐明。本研究探讨了尿毒酸代谢的新途径，即谷胱甘肽与尿毒酸的加成反应，形成谷胱甘肽-S偶联的咪唑类化合物(I)，并对其生理作用进行了研究。我们以前曾提出，这种代谢与阳光照射条件下表皮尿酸的跨顺式异构化和消除有关。所获得的新认识和结果如下：1、确定了化合物I的另外三个代谢物，并建立了新的代谢途径；2、化合物I及其代谢产物在其分子骨架的咪唑丙酸部分具有不对称的β-碳原子，即每个代谢物存在两个非对映异构体；3、制备了每个代谢物的两个非对映异构体，并用离子交换器纯化，并用理化分析进行了表征；4、建立了毛细管电泳法同时测定非对映异构体的新方法，该方法实现了对其分子的β-碳原子上立体异构体的酶识别；5.阐明了化合物I对γ-谷氨酰转移酶活性的强烈抑制作用，这涉及化合物I在阳光照射条件下形成的生理意义，可能是为了增加细胞内和/或细胞外谷胱甘肽的水平，并保护组织免受阳光引起的氧化应激或损伤。

In the skin, only trans-urocanic acid is formed from L-histidine by histidine ammonia-lyase and then accumulated in epidermis because of the absence of urocanate hydratase from the skin. The epidermal urocanic acid isomerized to the cis isomer by ultraviolet light. However, physiological functions of the accumulation and of the isomerization have not been elucidated. This research deals with a new pathway of urocanic acid metabolism, which is initiated by the adduction of glutathione to urocanic acid to form a glutathione S-conjugated imidazole compound (I), and also with its physiological roles. We previously suggested that the metabolism related to the trans-cis isomerization and the elimination of the epidermal urocanic acid under conditions of sunlight irradation. New knowledges and results obtained are as follows : 1, Three additional metabolites of compound I were specified, and the new metabolic pathway has been established completely ; 2, Compound I and its metabolites located in the pathway have an asymmetric beta-carbon atom on the skeletal imidazolepropanoate part of their molecules, i.e., the existance of two diastereomers of each metabolite ; 3, The two diastereomers of each metabolite were prepared, purified by ion-exchangers, and characterizad by physicochemical analyzes ; 4, A new method for simultaneous determination of the diastereomers was developed by capillary electrophoresis, and this method achieved characterization of the enzymatic recognition of stereoisomerism on the beta-carbon atom of their molecules ; 5, A great inhibitory effect of compound I on gamma-glutamyltransferase activity was elucidated and this involves a physiological importance of the formation of compound I under conditions of sunlight irradiation probably to increase intracellular and/or extracellular levels of glutathione, and to protect from oxidative stresses or damages in tissues caused by sunlight.