Arfsten Darryl P, Johnson Eric W, Wilfong Erin R, Jung Anne E, Bobb Andrew J
Naval Health Research Center Environmental Health Effects Laboratory, WPAFB, Ohio, USA.
Cutan Ocul Toxicol. 2007;26(2):113-34. doi: 10.1080/15569520701212233.
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 (14)C-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 + (14)C-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 + (14)C-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.
通过口服灌胃对Sprague-Dawley大鼠单次和多次给予N-乙酰-L-半胱氨酸（NAC）后，研究了放射性标记的NAC的分布及其对谷胱甘肽（GSH）代谢的影响。给予（14）C-NAC后，放射性在给药后1小时内分布到大多数检测组织，放射性水平在1小时至4小时内达到峰值，并且对于大多数检测组织，放射性在长达12小时或更长时间内保持升高。在第一次给药4小时后给予第二剂1200mg/kg NAC +（14）C-NAC，肝脏、肾脏、皮肤、胸腺、脾脏、眼睛和血清中的放射性显著超过单次给药后的水平。在第二剂给药4小时后给予第三剂1200mg/kg NAC +（14）C-NAC，除皮肤外，未进一步显著增加组织放射性。给予一剂1200mg/kg NAC后，皮肤中的GSH浓度增加20%，肝脏中增加50%，而肺和肾脏中的GSH未受影响。在第一次给药后4小时和8小时给予第二剂和第三剂1200mg/kg NAC，除皮肤GSH水平升高至与单次给予NAC后相似的水平外，未使组织GSH浓度高于基线水平。给予一剂1200mg/kg NAC后，肾脏中的谷胱甘肽-S-转移酶（GST）活性增加150%，肝脏中增加10%，皮肤中降低60%，对肺GST活性无影响。在第一次给药4小时后给予第二剂1200mg/kg NAC，皮肤GST活性进一步降低20%，而肾脏GST活性保持在与单次给予NAC后相似的升高水平。在第二剂给药4小时后给予第三剂NAC，与基线相比，肝脏GST活性显著增加，但不影响皮肤、肾脏或肺的GST活性。与重复给予1200mg/kg NAC相关，在皮肤和肾脏中检测到谷胱甘肽还原酶（GR）活性短暂降低。皮肤、肾脏和肝脏中的谷胱甘肽过氧化物酶（GxP）活性增加，表明在重复给予NAC后这些组织中发生了氧化应激。总体而言，本研究结果表明，NAC有可能通过提高组织NAC和/或半胱氨酸水平、GSH浓度和GST活性，在预防或降低某些组织中与接触化学刺激物（特别是硫芥）相关的毒性方面提供一些益处。然而，需要在动物中进行后续研究，以确认口服单次和多次剂量的NAC可显著降低与硫芥暴露相关的皮肤、眼睛和肺部毒性。重复给予NAC后GxP活性虽短暂升高，这一发现表明重复给予NAC可能在某些组织中诱导氧化应激，需要进一步研究来证实这一发现。
