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首页> 外文期刊>The Journal of toxicological sciences >Resistance to the skeletal muscle injury expressed by repeated treatment with compound A that has HMG-CoA reductase inhibitory activity.
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Resistance to the skeletal muscle injury expressed by repeated treatment with compound A that has HMG-CoA reductase inhibitory activity.

机译：对具有HMG-CoA还原酶抑制活性的化合物A重复治疗所表现出的对骨骼肌损伤的抵抗力。

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It has been noted that chemical-induced initial insult is sometimes no longer detected in examinations after additional consecutive treatments, suggesting that the target organs acquire resistance to the chemical toxicity. In this study, whether acquired resistance to the skeletal muscle toxicity is observed during repeated treatment of a toxic dose of Compound A that has a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitory activity was examined. F344 male rats (7-weeks old) were given a mixed diet with 0.12% Compound A (corresponding to approximately 100 mg/kg/day) for up to 56 days. Blood samples were obtained from the tail vein periodically during the dosing period, and utilized for the measurement of creatine kinase (CK) as a marker of skeletal muscle injury. In the necropsies on Days 4, 8, 11, 28, 42 and 56, the skeletal muscles from the rectus femoris were removed for histopathology or gene expression analysis. A satellite group was provided to measure the plasma concentrations of Compound A and M1, the active metabolite of Compound A. CK levels increased from Day 9 and reached approximately 30 times those of the controls on Day 12. Histopathology of the skeletal muscle on Day 11 revealed severe necrosis of the muscle fibers. However, in spite of continuous treatments to the damaged rats, the CK levels decreased after that and returned to normal levels on Day 18. No skeletal muscle injury was observed on Days 42 and 56. There were no marked differences in the exposure levels of Compound A and M1 between Days 8 (prior to CK elevation) and 28 (post CK elevation). As for the most significant changes in the gene expression analysis for the skeletal muscle on Days 42 and 56, the probe for IkappaBa, which is known as an inhibitor for nuclear factor-kappaB (NF-kappaB), increased 2-fold compared to the control. Furthermore, an increased probe for CCAAT/enhancer-binding protein (C/EBP) delta, a transcriptional factor, and a decreased probe for cAMP-response element-binding protein (CBP)/p300, a transcriptional coactivator, were also noted significantly on Day 56. These changes in the gene expression analysis suggested suppressed NF-kappaB-mediated transactivation, which was responsible for the protective effects on the muscle injury. Based on the present findings, the resistance to skeletal muscle injury observed in this study may be attributable to the suppressed NF-kappaB-mediated transactivation, but not to the decreased exposure to toxicants.
机译：已经注意到，在进行了额外的连续治疗后，有时在检查中不再检测到化学诱导的初始侮辱，这表明靶器官获得了对化学毒性的抵抗力。在这项研究中，检查了在重复处理具有3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制活性的有毒剂量的化合物A期间是否观察到对骨骼肌毒性的获得性抗性。给F344雄性大鼠（7周大）混合饮食含0.12％的化合物A（相当于约100 mg / kg /天），最多56天。在给药期间定期从尾静脉采集血样，并用于测量肌酸激酶（CK）作为骨骼肌损伤的标志。在第4、8、11、28、42和56天的尸检中，从股直肌中取出骨骼肌进行组织病理学或基因表达分析。提供了一个附属小组来测量化合物A和M1的血浆浓度，化合物A的活性代谢产物。CK水平从第9天开始增加，并在第12天达到对照水平的约30倍。骨骼肌的病理学在第11天。显示肌肉纤维严重坏死。然而，尽管对受损大鼠进行了连续治疗，其后CK水平仍下降并在第18天恢复正常水平。在第42天和第56天未观察到骨骼肌损伤。化合物的暴露水平无明显差异。在第8天（CK升高之前）和第28天（CK升高之后）之间的A和M1。至于第42天和第56天骨骼肌基因表达分析中最显着的变化，与已知的IkappaBa探针相比，IkappaBa的探针增加了2倍，IkappaBa被称为核因子-kappaB（NF-kappaB）抑制剂。控制。此外，还发现在CCAAT /增强子结合蛋白（C / EBP）δ（转录因子）上增加了探针，在cAMP反应元件结合蛋白（CBP）/ p300（转录共激活因子）上减少了探针。第56天。基因表达分析中的这些变化表明，NF-κB介导的反式激活受到抑制，这是对肌肉损伤的保护作用。基于目前的发现，在这项研究中观察到的对骨骼肌损伤的抵抗力可能归因于抑制的NF-κB介导的反式激活，而不是归因于减少的有毒物质暴露。

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