Robinson Corie N, Latimer Brian, Abreo Fleurette, Broussard Kiera, McMartin Kenneth E
a Department of Pharmacology, Toxicology and Neuroscience , Louisiana State University Health Sciences Center - Shreveport , Shreveport , LA , USA.
b Department of Pathology , Louisiana State University Health Sciences Center - Shreveport , Shreveport , LA , USA.
Clin Toxicol (Phila). 2017 Mar;55(3):196-205. doi: 10.1080/15563650.2016.1271128. Epub 2017 Jan 11.
Diglycolic acid (DGA) is one of the two primary metabolites of diethylene glycol (DEG). DEG is an industrial solvent that has been implicated in mass poisonings resulting from product misuse in the United States and worldwide, with the hallmark toxicity being acute kidney injury, hepatotoxicity, encephalopathy and peripheral neuropathy. Our laboratory has generated in-vitro evidence suggesting that DGA is the metabolite responsible for the proximal tubule necrosis and decreased kidney function observed following DEG ingestion. Furthermore, we have shown that DGA specifically accumulates in kidney tissues (100× higher than peak blood concentrations) following DEG administration.
To examine renal and hepatic accumulation and dysfunction following direct administration of DGA in-vivo. We hypothesize that administration of DGA will result in renal and hepatic DGA accumulation, as well as proximal tubular necrosis and liver injury.
Adult male Wistar rats were divided into three groups dosed with 0, 100 or 300 mg/kg DGA via single oral gavage. Urine was collected every 6-12 h and blood, kidneys and liver were removed upon sacrifice at 48 h post-dosing for analysis.
DGA accumulated significantly in both kidney and liver tissue only at 300 mg DGA/kg. DGA concentrations in the kidneys and liver correlated with renal and hepatic injury, respectively. Histopathological and clinical chemistry analysis revealed that DGA-treated animals exhibited moderate liver fatty accumulation and marked renal injury, again only at 300 mg/kg.
DGA-induced kidney injury demonstrated a steep dose response threshold, where severe damage occurred only in animals given 300 mg/kg DGA, while no toxicity was observed at 100 mg/kg.
These results provide evidence for in-vivo toxicity following direct administration of DGA, a metabolite of DEG. The steep dose-response threshold for toxicity suggests mechanistically that there is likely a saturable step that results in DGA accumulation in target organs.
二甘醇酸（DGA）是二甘醇（DEG）的两种主要代谢产物之一。DEG是一种工业溶剂，在美国和全球范围内，因产品误用导致了多起大规模中毒事件，其标志性毒性为急性肾损伤、肝毒性、脑病和周围神经病变。我们实验室已获得体外证据，表明DGA是DEG摄入后导致近端肾小管坏死和肾功能下降的代谢产物。此外，我们还表明，给予DEG后，DGA特异性地在肾组织中蓄积（比血药浓度峰值高100倍）。
研究直接体内给予DGA后肾脏和肝脏的蓄积及功能障碍情况。我们假设给予DGA会导致肾脏和肝脏中DGA蓄积，以及近端肾小管坏死和肝损伤。
成年雄性Wistar大鼠分为三组，通过单次灌胃给予0、100或300mg/kg DGA。每6 - 12小时收集尿液，给药后48小时处死动物，取出血液、肾脏和肝脏进行分析。
仅在给予300mg DGA/kg时，DGA在肾脏和肝脏组织中显著蓄积。肾脏和肝脏中的DGA浓度分别与肾损伤和肝损伤相关。组织病理学和临床化学分析显示，仅在给予300mg/kg时，DGA处理的动物出现中度肝脏脂肪蓄积和明显的肾损伤。
DGA诱导的肾损伤表现出陡峭的剂量反应阈值，即仅在给予300mg/kg DGA的动物中出现严重损伤，而在100mg/kg时未观察到毒性。
这些结果为直接给予DEG的代谢产物DGA后的体内毒性提供了证据。毒性的陡峭剂量反应阈值从机制上表明，可能存在一个饱和步骤导致DGA在靶器官中蓄积。
