EFFECTS OF N-ACETYLCYSTEINE STEREOISOMERS ON OXYGEN-INDUCED LUNG INJURY IN RATS

The effects of the stereoisomers of N-acetylcysteine (L-NAC and D-NAC) on oxygen-induced lung oedema have been studied in rats. The NAC-isom ers were given by an osmotic minipump in order to attain continuous ad ministration, either intravenously or intragastrically, In some experi ments, plasma concentrations of NAG, cysteine and glutathione (total c oncentrations, i.e., concentrations obtained after reduction of the sa mples with dithiothreitol) were recorded. Exposure to oxygen induced a n almost two-fold increase of the lung wet weight. When L-NAC or D-NAC were given intravenously, in doses of 1.1 mmol/day/kg body weight, th e increase of lung wet weight was prevented by 40-50%, The plasma conc entrations were approximate to 40 mu M (L-NAC) and approximate to 90 m u M (D-NAC). Following intragastrical administration of the same doses , plasma concentrations of L-NAC and D-NAC reached approximate to 3 an d approximate to 60 mu M, respectively. Using this method of administr ation, only D-NAC significantly diminished the increase of the lung we t weight. The difference in plasma concentrations of the NAC isomers, particularly after intragastric administration, most likely reflects t he fact that L-NAC is effectively hydrolysed in most tissues, while D- NAC is resistant to enzymatic hydrolysis, thus penetrating largely int act into the systemic circulation. The data presented shows that NAG, regardless of stereoconfiguration, will protect the lung against oxyge n toxicity, provided sufficient systemic levels are obtained, Since D- NAC is not a precursor of L-cysteine, formation of glutathione cannot explain the protective effects of this isomer. L- and D-NAC may theref ore act via direct antioxidant/radical scavenging mechanisms and not n ecessarily as precursors of glutathione in this model.