Devi Sachin S, Philip Binu K, Warbritton Alan, Latendresse John R, Mehendale Harihara M
Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, 700 University Ave, Monroe, LA 71209, USA.
Toxicology. 2006 Sep 21;226(2-3):107-17. doi: 10.1016/j.tox.2006.06.007. Epub 2006 Jun 16.
Previously, we reported that an ordinarily non-lethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic rats due to inhibited liver tissue repair, whereas 30 mg TA/kg allows 100% survival due to stimulated although delayed tissue repair. Objective of this investigation was to test whether prior administration of a low dose of TA (30 mg/kg) would lead to sustainable stimulation of liver tissue repair in type 1 diabetic rats sufficient to protect from a subsequently administered lethal dose of TA. Therefore, in the present study, the hypothesis that preplacement of tissue repair by a low dose of TA (30 mg TA/kg, ip) can reverse the hepatotoxicant sensitivity (autoprotection) in type 1 diabetic rats was tested. Preliminary studies revealed that a single intraperitoneal (ip) administration of TA causes 90% mortality in diabetic rats with as low as 75 mg/kg. To establish an autoprotection model in diabetic condition, diabetic rats were treated with 30 mg TA/kg (priming dose). Administration of priming dose stimulated tissue repair that peaked at 72h, at which time these rats were treated with a single ip dose of 75 mg TA/kg. Our results show that tissue repair stimulated by the priming dose enabled diabetic rats to overexpress, calpastatin, endogenous inhibitor of calpain, to inhibit calpain-mediated progression of liver injury induced by the subsequent administration of lethal dose, resulting in 100% survival. Further investigation revealed that protection observed in these rats is not due to decreased bioactivation. These studies underscore the importance of stimulation of tissue repair in the final outcome of liver injury (survival/death) after hepatotoxicant challenge. Furthermore, these results also suggest that it is possible to stimulate tissue repair in diabetics to overcome the enhanced sensitivity of hepatotoxicants.
此前，我们报道过，通常非致死剂量的硫代乙酰胺（TA，300毫克/千克）会导致1型糖尿病大鼠90%的死亡率，原因是肝组织修复受到抑制；而30毫克TA/千克的剂量则能使100%的大鼠存活，因为组织修复虽有延迟但受到了刺激。本研究的目的是测试预先给予低剂量TA（30毫克/千克）是否会导致1型糖尿病大鼠肝组织修复得到持续刺激，从而足以使其免受随后给予的致死剂量TA的影响。因此，在本研究中，我们测试了低剂量TA（30毫克TA/千克，腹腔注射）预先启动组织修复能否逆转1型糖尿病大鼠对肝毒性物质的敏感性（自身保护）这一假设。初步研究表明，单次腹腔注射TA，低至75毫克/千克时就会导致糖尿病大鼠90%的死亡率。为了建立糖尿病状态下的自身保护模型，给糖尿病大鼠注射30毫克TA/千克（启动剂量）。启动剂量的注射刺激了组织修复，在72小时达到峰值，此时给这些大鼠单次腹腔注射75毫克TA/千克。我们的结果表明，启动剂量刺激的组织修复使糖尿病大鼠能够过度表达钙蛋白酶抑制蛋白（钙蛋白酶的内源性抑制剂），以抑制随后给予致死剂量所诱导的钙蛋白酶介导的肝损伤进展，从而使100%的大鼠存活。进一步研究表明，这些大鼠中观察到的保护作用并非由于生物活化降低。这些研究强调了在肝毒性物质攻击后，刺激组织修复对肝损伤最终结果（存活/死亡）的重要性。此外，这些结果还表明，刺激糖尿病患者的组织修复以克服对肝毒性物质的增强敏感性是可能的。
