Jösch C, Sies H, Akerboom T P
Institut für Physiologische Chemie I, Heinrich-Heine-Universität, Düsseldorf, Germany.
Biochem Pharmacol. 1998 Sep 15;56(6):763-71. doi: 10.1016/s0006-2952(98)00065-3.
The role of cysteinylglycine S-conjugate dipeptidases in the intrahepatic mercapturic acid pathway was investigated in rat liver. Subcellular compartmentation studies and liver perfusions were performed using monochlorobimane and bimane S-conjugates as model compounds. The major part (over 95%) of total hepatic cysteinylglycine S-conjugate dipeptidase activity was located in the cytosol. Lower specific activity appeared in the canalicular plasma membrane fraction. Similar hepatic localization of dipeptidase activity was seen in the guinea pig. In intact rat liver perfused with monochlorobimane, the major products were the glutathione S-conjugate (mBSG) and the cysteinylglycine S-conjugate (mBCG) in bile. Minor amounts of the cysteine S-conjugate (mBCys) and the mercapturic acid (mBNAc) were formed, indicating a limitation in further metabolism of the dipeptide S-conjugate in the biliary space. However, when the dipeptide S-conjugate was offered to the sinusoidal space in liver perfusions, substantial uptake and conversion to mBNAc was observed, and only trace amounts of the infused dipeptide appeared in bile. The data suggest that cytosolic cysteinylglycine S-conjugate dipeptidase as identified here is involved in hepatic mercapturic acid formation from sinusoidal cysteinylglycine S-conjugates. This is especially of significance for species such as guinea pig and human, in which dipeptide S-conjugates are generated in the sinusoidal domain of the liver due to the presence of high gamma-glutamyltranspeptidase activity.
在大鼠肝脏中研究了半胱氨酰甘氨酸S-共轭二肽酶在肝内硫醚氨酸途径中的作用。使用一氯联苯胺和联苯胺S-共轭物作为模型化合物进行亚细胞分级研究和肝脏灌注。肝脏中总半胱氨酰甘氨酸S-共轭二肽酶活性的主要部分（超过95%）位于胞质溶胶中。在胆小管质膜部分出现较低的比活性。在豚鼠中也观察到二肽酶活性的类似肝脏定位。在用一氯联苯胺灌注的完整大鼠肝脏中，胆汁中的主要产物是谷胱甘肽S-共轭物（mBSG）和半胱氨酰甘氨酸S-共轭物（mBCG）。形成少量的半胱氨酸S-共轭物（mBCys）和硫醚氨酸（mBNAc），表明胆汁空间中二肽S-共轭物的进一步代谢存在限制。然而，当在肝脏灌注中将二肽S-共轭物提供给肝血窦空间时，观察到大量摄取并转化为mBNAc，并且注入的二肽仅以痕量出现在胆汁中。数据表明，此处鉴定的胞质半胱氨酰甘氨酸S-共轭二肽酶参与了肝血窦半胱氨酰甘氨酸S-共轭物形成肝内硫醚氨酸的过程。这对于豚鼠和人类等物种尤为重要，由于存在高γ-谷氨酰转肽酶活性，这些物种在肝脏的肝血窦区域会产生二肽S-共轭物。
