UPTAKE AND DISTRIBUTION OF N-ACETYLCYSTEINE IN MICE - TISSUE-SPECIFIC EFFECTS ON GLUTATHIONE CONCENTRATIONS
UPTAKE AND DISTRIBUTION OF N-ACETYLCYSTEINE IN MICE - TISSUE-SPECIFIC EFFECTS ON GLUTATHIONE CONCENTRATIONS
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DOI：
10.1093/carcin/16.9.2099
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发表时间：
1995-09-01
期刊：
影响因子：
4.7
通讯作者：
WOLF, CR
中科院分区：
文献类型：
--
作者：
MCLELLAN, LI;LEWIS, AD;WOLF, CR
细胞硫醇的调节已被用于减轻与癌症化疗相关的毒副作用，目前正在被研究为癌症治疗的一种新的治疗策略。N-乙酰半胱氨酸(NAC)是研究最广泛的硫醇水平调节剂之一，它是一种细胞保护药物，具有多种治疗应用，包括用作癌症化疗的辅助药物。以前，当NAC与化疗烷化剂联合使用时，已经观察到了组织特异性保护作用，但其基础尚不清楚。鉴于NAC在膀胱和骨髓中的细胞保护作用不同，我们考察了该化合物对小鼠肝脏、膀胱和骨髓谷胱甘肽(GSH)水平的影响，以及C-14标记的NAC的分布。除脑和脊髓外，大多数组织以不同的速度和水平摄取了放射性标记的NAC。膀胱、骨髓和肝脏均在注射后15min内摄取药物或其代谢物，NAC对肝脏GSH浓度无明显影响，但使膀胱GSH水平增加近2倍。而给予NAC后，小鼠骨髓中GSH含量下降70-50%。当检查不同的骨髓细胞群时，GSH的降低与粒细胞相关，而不是与淋巴细胞相关，后者的GSH水平保持不变。这些发现为NAC不同的细胞保护作用提供了可能的解释。
Modulation of cellular thiols has been used to ameliorate the toxic side effects associated with cancer chemotherapy and is currently being investigated as a novel therapeutic strategy in cancer treatment. One of the most extensively studied modulators of thiol levels is N-acetylcysteine (NAC), a cytoprotective drug with multiple therapeutic applications, including use as an adjunct to cancer chemotherapy. Tissue-specific protective effects have previously been observed when NAC has been used in conjunction with chemotherapeutic alkylating agents, but the basis for this was unknown. In view of the contrasting cytoprotective effects of NAC in bladder and bone marrow we examined the effect of this compound on mouse liver, bladder and bone marrow glutathione (GSH) levels, as well as the disposition of C-14-labelled NAC. Radiolabelled NAC was taken up by the majority of tissues at varying rates and levels, except for the brain and spinal cord. The bladder, bone marrow and liver all took up the drug or its metabolites within 15 min of injection, NAC was not found to alter GSH concentrations in the liver, but increased GSH levels in the bladder similar to 2-fold. In contrast, the GSH content of bone marrow was found to decrease by 70-50% after NAC administration. When separate bone marrow cell populations were examined the decrease in GSH was associated with granulocytes, as opposed to lymphocytes, whose GSH levels remained unchanged. These findings provide a possible explanation for the differential cytoprotective effects of NAC.