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-isomers were given by an osmotic minipump in order to attain continuous administration, either intravenously or intragastrically. In some experiments, plasma concentrations of NAC, cysteine and glutathione (total concentrations, i.e., concentrations obtained after reduction of the samples with dithiothreitol) were recorded. Exposure to oxygen induced an almost two-fold increase of the lung wet weight. When L-NAC or D-NAC were given intravenously, in dose of 1.1 mmol/day/kg body weight, the increase of lung wet weight was prevented by 40-50%. The plasma concentrations were approximately 40 microM (L-NAC) and approximately 90 microM (D-NAC). Following intragastrical administration of the same doses, plasma concentrations of L-NAC and D-NAC reached approximately 3 and approximately 60 microM, respectively. Using this method of administration, only D-NAC significantly diminished the increase of the lung wet weight. The difference in plasma concentrations of the NAC isomers, particularly after intragastric administration, most likely reflects the fact that L-NAC is effectively hydrolysed in most tissues, while D-NAC is resistant to enzymatic hydrolysis, thus penetrating largely intact into the systemic circulation. The data presented shows that NAC, regardless of stereoconfiguration, will protect the lung against oxygen 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 therefore act via direct antioxidant/radical scavenging mechanisms and not necessarily as precursors of glutathione in this model.
Särnstrand
B
B
Department of Pharmacology, Astra Draco AB, Lund, Sweden.
Tunek
A
A
Sjödin
K
K
Hallberg
A
A
D000111:Acetylcysteine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D003545:Cysteine / Q000097:blood; D004195:Disease Models, Animal; D005978:Glutathione / Q000097:blood; D006940:Hyperemia / Q000188:drug therapy; D015918:Infusion Pumps, Implantable; D007262:Infusions, Intravenous; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009995:Osmosis; D010100:Oxygen / Q000633:toxicity*; D011654:Pulmonary Edema / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D005978:Glutathione; D003545:Cysteine; D010100:Oxygen; D000111:Acetylcysteine