Diet restriction enhances compensatory liver tissue repair and survival following administration of lethal dose of thioacetamide.
Diet restriction enhances compensatory liver tissue repair and survival following administration of lethal dose of thioacetamide.
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饮食限制可增强给予致死剂量的硫代乙酰胺后的代偿性肝组织修复和存活。
DOI：
10.1006/taap.1998.8365
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发表时间：
1998
影响因子：
3.8
通讯作者：
Mehendale,HM
中科院分区：
文献类型：
--
作者：
Ramaiah,SK;Soni,MG;Bucci,TJ;Mehendale,HM
众所周知，饮食限制可以预防包括癌症在内的大量与年龄相关的疾病。然而，饮食限制对非癌症终点的影响尚不清楚。本研究的目的是调查饮食限制是否可以防止硫代乙酰胺（TA）的肝毒性，如果是这样的话，探讨其潜在的机制。将雄性Sprague-Dawley大鼠（250-275 g）维持在其自由采食量（AL）的65%，持续3周，然后用50 mg TA/kg的单次低剂量ip处理。在TA给药后0-120 h测定血浆酶（ALT和SDH）、肝糖原水平和3 H-胸苷掺入肝细胞核DNA。肝切片进行组织病理学检查，并通过增殖细胞核抗原（PCNA）免疫组化评估细胞周期进展。在AL大鼠中，肝坏死在12 h明显，在36 h达到峰值，持续至72 h，并在96 h消退。在饮食限制（DR）组中，在12 h观察到肝坏死，在24 h达到峰值，持续至72 h，并在96 h消退。最大的损伤所示的酶升高发生在DR大鼠，约6倍以上，在AL组中观察到的。肝脏切片的组织学检查显示肝损伤与血浆酶升高一致。与AL组相比，DR组大鼠的S期合成更高且持续。在DR大鼠中，S期刺激在36 h明显，在48 h达到峰值，并持续到96 h，而在AL大鼠中，S期刺激在36 h达到峰值，并在72 h消退。PCNA研究显示，相应的刺激细胞周期的进展，表明高度刺激的代偿性组织修复。14天致死率实验（600 mg TA/kg ip）表明，DR大鼠的存活率为70%，而AL组为10%。虽然饮食限制增加TA的肝毒性损伤，但它通过增强肝组织修复来保护致死性结果。采用等毒性剂量（AL大鼠中600 mg TA/kg产生的肝损伤与DR大鼠中50 mg TA/kg观察到的肝损伤相似）对肝损伤和组织修复的比较显示，尽管在长达36小时内损伤几乎相等，但DR大鼠中的组织修复反应要高得多。代偿性组织修复使DR大鼠免于死亡，而AL大鼠的代偿性低得多，导致肝损伤进展，最终死亡。
Diet restriction is known to prevent a plethora of age-associated diseases including cancer. However, the effects of diet restriction on noncancer end points are not known. The objective of this study was to investigate whether diet restriction protects against hepatotoxicity of thioacetamide (TA), and if so, to investigate the underlying mechanism. Male Sprague–Dawley rats (250–275 g) were maintained on 65% of theirad libitum(AL) food consumption for a period of 3 weeks and then treated with a single low dose of 50 mg TA/kg ip. Plasma enzymes (ALT and SDH), hepatic glycogen levels, and3H-thymidine incorporation into hepatocellular nuclear DNA were measured during a time course (0–120 h) after TA administration. Liver sections were examined for histopathology, and cell-cycle progression was assessed by proliferating cell nuclear antigen (PCNA) immunohistochemistry. In AL rats hepatic necrosis was evident at 12 h, peaked at 36 h, persisted up to 72 h, and was resolved by 96 h. In the diet-restricted (DR) group hepatic necrosis was observed at 12 h, peaked at 24 h, persisted till 72 h, and was resolved by 96 h. Maximal injury indicated by enzyme elevation occurred in DR rats and was approximately sixfold greater than that observed in the AL group. Histopathological examination of the liver sections revealed liver injury concordant with plasma enzyme elevations. There was a higher and sustained S-phase synthesis in the DR rats compared to AL group. S-phase stimulation was evident at 36 h, peaked at 48 h, and persisted until 96 h in the DR rats, whereas in the AL rats peak S-phase stimulation occurred at 36 h and subsided by 72 h. PCNA studies revealed a corresponding stimulation of cell-cycle progression indicating highly stimulated compensatory tissue repair. The 14-day lethality experiments (600 mg TA/kg ip) indicated 70% survival in the DR rats compared to 10% survival in the AL group. Although diet restriction increases hepatotoxic injury of TA, it protects from the lethal outcome by enhanced liver tissue repair. Comparison of liver injury and tissue repair employing an equitoxic dose (600 mg TA/kg in AL rats yields similar liver injury as observed with 50 mg TA/kg in DR rats) revealed that in spite of near equal injury up to 36 h, tissue repair response in DR rats is much higher. The compensatory tissue repair allows the DR rats to escape death in contrast to much lower compensation in AL rats leading to progression of liver injury culminating in death.
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DOI：
10.1093/jn/117.2.286
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DOI：
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