Wang T, Fontenot R D, Soni M G, Bucci T J, Mehendale H M
Department of Toxicology, The University of Louisiana at Monroe, Monroe, Louisiana 71209, USA.
Toxicol Appl Pharmacol. 2000 Jul 15;166(2):92-100. doi: 10.1006/taap.2000.8952.
Diabetes is known to potentiate thioacetamide (TA)-induced liver injury via enhanced bioactivation. Little attention has been given to the role of compensatory tissue repair on ultimate outcome of hepatic injury in diabetes. The objective of this study was to investigate the effect of diabetes on TA-induced liver injury and lethality and to investigate the underlying mechanisms. We hypothesized that hepatotoxicity of TA in diabetic rats would increase due to enhanced bioactivation-mediated liver injury and also due to compromised compensatory tissue repair, consequently making a nonlethal dose of TA lethal. On day 0, male Sprague-Dawley rats (250-300 g) were injected with streptozotocin (STZ, 60 mg/kg ip) to induce diabetes. On day 10 the STZ-induced diabetic rats and the nondiabetic rats received a single dose of TA (300 mg/kg ip). This normally nonlethal dose of TA caused 90% mortality in the STZ-induced diabetic rats. At various times (0-60 h) after TA administration, liver injury was assessed by plasma alanine aminotransferase (ALT), sorbitol dehydrogenase (SDH), and liver histopathology. Liver function was evaluated by plasma bilirubin. Cell proliferation and tissue repair were evaluated by [(3)H]thymidine ((3)H-T) incorporation and proliferating cell nuclear antigen (PCNA) assays. In the nondiabetic rat, liver necrosis peaked at 24 h and declined thereafter toward normal by 60 h. In the STZ-induced diabetic rat, however, liver necrosis was significantly increased from 12 h onward and progressed, culminating in liver failure and death. Liver tissue repair studies showed that, in the liver of nondiabetic rats, S-phase DNA synthesis was increased at 36 h and peaked at 48 h following TA administration. However, DNA synthesis was approximately 50% inhibited in the liver of diabetic rats. PCNA study showed a corresponding decrease of cell-cycle progression, indicating that the compensatory tissue repair was sluggish in the diabetic rats. Further investigation of tissue repair by employing equitoxic doses (300 mg TA/kg in the non-diabetic rats; 30 mg TA/kg in the diabetic rats) revealed that, despite equal injury up to 24 h following injection, the tissue repair response in the diabetic rats was much delayed. The compromised tissue repair prolonged liver injury in the diabetic rats. These studies suggest that the increased TA hepatotoxicity in the diabetic rat is due to combined effects of increased bioactivation-mediated liver injury of TA and compromised compensatory tissue repair.
已知糖尿病会通过增强生物活化作用来增强硫代乙酰胺（TA）诱导的肝损伤。然而，对于代偿性组织修复在糖尿病肝损伤最终结局中的作用却很少有人关注。本研究的目的是调查糖尿病对TA诱导的肝损伤和致死率的影响，并探究其潜在机制。我们假设，糖尿病大鼠中TA的肝毒性会增加，这是由于生物活化介导的肝损伤增强，以及代偿性组织修复受损，从而使原本非致死剂量的TA变得致命。在第0天，给雄性Sprague-Dawley大鼠（250 - 300克）腹腔注射链脲佐菌素（STZ，60毫克/千克）以诱导糖尿病。在第10天，STZ诱导的糖尿病大鼠和非糖尿病大鼠接受单次剂量的TA（300毫克/千克腹腔注射）。这个通常非致死剂量的TA在STZ诱导的糖尿病大鼠中导致了90%的死亡率。在给予TA后的不同时间（0 - 60小时），通过血浆丙氨酸氨基转移酶（ALT）、山梨醇脱氢酶（SDH）以及肝脏组织病理学评估肝损伤。通过血浆胆红素评估肝功能。通过[³H]胸腺嘧啶核苷（³H-T）掺入和增殖细胞核抗原（PCNA）检测评估细胞增殖和组织修复。在非糖尿病大鼠中，肝坏死在24小时达到峰值，此后到60小时逐渐恢复正常。然而，在STZ诱导的糖尿病大鼠中，肝坏死从12小时起显著增加并持续进展，最终导致肝衰竭和死亡。肝脏组织修复研究表明，在非糖尿病大鼠肝脏中，TA给药后36小时S期DNA合成增加，并在48小时达到峰值。然而，糖尿病大鼠肝脏中的DNA合成受到了约50%的抑制。PCNA研究显示细胞周期进程相应减少，表明糖尿病大鼠的代偿性组织修复缓慢。通过使用等效毒性剂量（非糖尿病大鼠中为300毫克TA/千克；糖尿病大鼠中为30毫克TA/千克）进一步研究组织修复发现，尽管注射后24小时内损伤程度相同，但糖尿病大鼠的组织修复反应明显延迟。受损的组织修复延长了糖尿病大鼠的肝损伤时间。这些研究表明，糖尿病大鼠中TA肝毒性增加是由于TA生物活化介导的肝损伤增加以及代偿性组织修复受损共同作用的结果。
