Endotoxin detoxification by alkaline phosphatase in cholestatic liversPoelstra, K., Bakker, WW., Hardonk, MJ. & Meijer, DKF., 1997, CELLS OF THE HEPATIC SINUSOID, VOL 6. Wisse, E., Knook, DL. & Balabaud, C. (eds.). LEIDEN: The Kupffer Cell Foundation, p. 187-190 4 p.
Research output: Chapter in Book/Report/Conference proceeding › Conference contribution › Academic › peer-review
Increased expression of alkaline phosphatase (AP) in the liver is a hallmark of cholestasis but the pathophysiological role of this is not clear. We argue that deprotonation of carboxyl groups at the active site of the enzyme may be a prerequisite for optimal AP activity. Such a creation of negative charged groups can he achieved at high pH levels, but may also be directly provided by exposure of AP to polyanionic molecules. Endotoxin is a phosphorylated substance with multiple negatively charged residues. Phosphate groups determine many biological activities of this molecule. Therefore, we tested whether AP is able to dephosphorylate endotoxin at a physiological pH level. Phosphatase activity was histochemically studied in livers from normal and bile duct ligated rats as well as in the intestine. Enzyme activity was studied at pH 9.0 according to standard procedures and at pH 7.3 using endotoxin from E.coli as substrate. Furthermore the effect of AP upon the toxicity of endotoxin was assessed in vivo. In these studies, endotoxin preparations were administered intradermally to endotoxin sensitisized rats. Part of these preparations were pretreated with AP with or without the AP inhibitor levamisole (n=6 per group). Subsequently, the dermis was removed and neutrophil influx was measured.
Our results show that hepatic and intestinal AP is endowed with endotoxin dephosphorylating activity at pH 7.4. Experiments also demonstrate that endotoxin pre-incubated with AP induced a much lower neutrophil influx as compared to endotoxin pre-incubated with vehicle (p <0.05). This effect was inhibitable by levamisole (p <0.025). Since cholestasis is associated with an increased delivery of endotoxin to the liver, endotoxin dephosphorylation may reflect an important function of this enzyme.
|Title of host publication||CELLS OF THE HEPATIC SINUSOID, VOL 6|
|Editors||E Wisse, DL Knook, C Balabaud|
|Place of Publication||LEIDEN|
|Publisher||The Kupffer Cell Foundation|
|Number of pages||4|
|Publication status||Published - 1997|
|Event||8th International Symposium on the Cells of the Hepatic Sinusoid - , France|
Duration: 1-Sep-1996 → 5-Sep-1996
|Other||8th International Symposium on the Cells of the Hepatic Sinusoid|
|Period||01/09/1996 → 05/09/1996|
8th International Symposium on the Cells of the Hepatic Sinusoid
01/09/1996 → 05/09/1996France