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
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
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DOI：
10.1080/15569520701212233
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发表时间：
2007-01-01
影响因子：
1.6
通讯作者：
Bobb, Andrew J.
中科院分区：
文献类型：
--
作者：
Arfsten, Darryl P.;Johnson, Eric W.;Bobb, Andrew J.
通过口服车库单次和多次给予 Sprague-Dawley 大鼠，研究了放射性标记 N-A 十六烷基-L-半胱氨酸 (NAC) 的分布及其对谷胱甘肽 (GSH) 代谢的影响。与施用C-14-NAC相关的放射性分布到施用后1小时内检查的大多数组织，峰值放射性水平出现在1小时至4小时内，并且对于大多数检查的组织，放射性保持升高长达12小时或更长时间。第一次给药后 4 小时，给予第二次 1,200 mg/kg NA C + C-14-NAC 剂量，肝脏、肾脏、皮肤、胸腺、脾脏、眼睛和血清放射性显着高于 I 剂量后达到的水平。第二次给药后 4 小时，给予第三次剂量 1,200 mg/kg NAC + C-14-NAC，除皮肤外，没有进一步显着增加组织放射性。一剂 1,200mg/kg NAC 后，皮肤中的 GSH 浓度增加 20%，肝脏中的 GSH 浓度增加 50%，而肺和肾中的 GSH 不受影响。在第一次给药后 4 小时和 8 小时给予第二次和第三次 1,200 mg/kg NAC 剂量时，组织 GSH 浓度并未增加至背景以上，但皮肤 GSH 水平升高至与单剂量 NAC 后获得的水平相似的水平。单剂量 1,200mg/kg NAC 后，肾脏中的谷胱甘肽-S-转移酶 (GST) 活性增加了 150%，肝脏中的谷胱甘肽-S-转移酶 (GST) 活性增加了 10%，皮肤中的谷胱甘肽-S-转移酶 (GST) 活性降低了 60%，并且对肺 GST 活性没有影响。第一次给药后 4 小时，给予第二剂 1,200mg/kg NAC，皮肤 GST 活性进一步降低 20%，而肾脏 GST 活性仍然升高，水平与 1 剂 NA C 后获得的水平相似。第二次给药后 4 小时，给予第三剂 NAC，与背景相比，肝脏 GST 活性显着增加，但不影响皮肤、肾脏或肺 GST 活性。在皮肤和肾脏中测量到与重复施用 1, 200 mg/kg NAC 相关的谷胱甘肽还原酶 (GR) 活性的短暂降低。在皮肤、肾脏和肝脏中谷胱甘肽过氧化物酶 (GxP) 活性增加，表明这些组织中发生了氧化应激，以响应重复施用 NAC。总体而言，本研究的结果表明，NAC 可以通过增加组织 NAC 和/或半胱氨酸水平、GSH 浓度和 GST 活性，在预防或减少某些组织中与化学刺激物（特别是硫芥）暴露相关的毒性方面提供一些益处。然而，需要对动物进行后续研究来证实口服单剂量和多剂量 NAC 可以显着降低与硫芥暴露相关的皮肤、眼睛和肺部毒性。重复施用 NAC 后 GxP 活性升高（尽管是短暂的）这一发现表明，重复施用 NAC 可能会在某些组织中诱导氧化应激，需要进一步的研究来证实这一发现。
The distribution of radio-labeled N-A cetyl-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 garage. Radioactivity associated with administration of C-14- NAC distributed to most tissues examined within I hour of administration with peak radioactivity levels occurring within I 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 NA C + C-14-NAC 4 hours after the first increased liver, kidney, skin, thymus, spleen, eye, and serum radioactivity significantly beyond levels achieved following I dose. Administration of a third dose of 1,200 mg/kg NAC + C-14-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 1,200mg/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 1,200mg/kg NAC. Administration of a second dose of 1,200mg/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 I dose of NA C. Administration of a third dose of NA C 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.