Distribution of Radio-Labeled N-Acetyl-L-Cysteine in Sprague-Dawley Rats and Its Effect on Glutathione Metabolism Following Single and Repeat Dosing by Oral Gavage

The distribution of radio-labeled N-Acetyl-L-Cysteine (NAC) and its impact on glutathione (GSH) metabolism was studied in Sprague-Dawley rats following single and multiple dosing with NAC by oral gavage. Radioactivity associated with administration of 14C-NAC distributed to most tissues examined within 1 hour of administration with peak radioactivity levels occurring within 1 hour to 4 hours and for a majority of the tissues examined, radioactivity remained elevated for up to 12 hours or more. Administration of a second dose of 1,200 mg/kg NAC + 14C-NAC 4 hours after the first increased liver, kidney, skin, thymus, spleen, eye, and serum radioactivity significantly beyond levels achieved following 1 dose. Administration of a third dose of 1,200 mg/kg NAC + 14C-NAC 4 hours after the second dose did not significantly increase tissue radioactivity further except in the skin. GSH concentrations were increased 20% in the skin and 50% in the liver after one dose of 1,200 mg/kg NAC whereas lung and kidney GSH were unaffected. Administration of a second and third dose of 1,200 mg/kg NAC at 4 hours and 8 hours after the first did not increase tissue GSH concentrations above background with the exception that skin GSH levels were elevated to levels similar to those obtained after a single dose of NAC. Glutathione-S-transferase (GST) activity was increased 150% in the kidney and 10% in the liver, decreased 60% in the skin, and had no effect on lung GST activity following a single dose of 1,200 mg/kg NAC. Administration of a second dose of 1,200 mg/kg NAC 4 hours after the first decreased skin GST activity a further 20% whereas kidney GST activity remained elevated at levels similar to those obtained after 1 dose of NAC. Administration of a third dose of NAC 4 hours after the second dose increased liver GST activity significantly as compared to background but did not affect skin, kidney, or lung GST activity. Transient decreases in glutathione reductase (GR) activity were measured in the skin and kidney in association with repeat administration of 1,200 mg/kg NAC. Glutathione peroxidase (GxP) activity was increased in the skin, kidney, and liver suggesting that oxidative stress was occurring in these tissues in response to repeat dosing with NAC. Overall, the results of this study present the possibility that NAC could provide some benefit in preventing or reducing toxicity related to exposure to chemical irritants (particularly sulfur mustard) in some tissues by increasing tissue NAC and/or cysteine levels, GSH concentrations, and GST activity. However, follow-on studies in animals are needed to confirm that oral administration of single and multiple doses of NAC can significantly reduce skin, eye, and lung toxicity associated with sulfur mustard exposure. The finding that GxP activity is elevated, albeit transiently, following repeat administration of NAC suggests that repeat administration of NAC may induce oxidative stress in some tissues and further studies are needed to confirm this finding.