Effects of hypochlorous acid and chloramines on vascular resistance, cell integrity, and biliary glutathione disulfide in the perfused rat liver: modulation by glutathione

Abstract

The accumulation of polymorphonuclear leucocytes (PMN) may play an important role in liver injury by toxins and ischemia/reperfusion. Upon activation these cells generate hypochlorous acid (HOCl) and long-lived oxidants such as monochloramine (NH2Cl) and taurinechloramine (TauNHCl) which could contribute to organ injury when PMN accumulate in the liver. Therefore, the effects of HOCl, NH2Cl and TauNHCl on hepatic function were investigated in the perfused rat liver. HOCl at a concentration of 2.7 microM resulted in a marked increase in the perfusion pressure and the release of LDH associated with a decrease in bile flow. These effects were abolished by increasing the concentration of extracellular glutathione in the perfusate to physiological levels. NH2Cl (15 microM) and TauNHCl (65 microM) increased the perfusion pressure only slightly, but resulted in significant increases in the biliary excretion of glutathione disulfide, indicating that chloramines are reduced intracellularly by glutathione. The increment in biliary glutathione disulfide depended on the amount of chloramine taken up by the liver. The extraction of NH2Cl averaged 98% compared to 13% for TauNHCl. The present data indicates that intra- and extracellular glutathione plays an important role not only in the detoxification of O2-. and H2O2 generated by activated PMN but also in the protection against the cytotoxic effects of products of myeloperoxidase released by PMN upon activation.