Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
Toxicol Sci. 2011 Oct;123(2):374-83. doi: 10.1093/toxsci/kfr197. Epub 2011 Jul 29.
Misuse of diethylene glycol (DEG) has led to numerous epidemic poisonings worldwide. DEG produces toxicity because of its metabolism, although the mechanism of its toxicity has not been further defined. The purpose of this study was to investigate the accumulation of specific metabolites in blood and target organ tissues and to determine the relationship between tissue accumulation of metabolites and the resulting toxicity. Wistar rats were treated with water, 2 g/kg DEG (low dose), 10 g/kg DEG (high dose), or 10 g/kg DEG + fomepizole (15 mg/kg then 10 mg/kg per 12 h, to inhibit DEG metabolism), and blood and tissue samples were collected up to 48 h. After high doses of DEG, 2-hydroxyethoxyacetic acid (HEAA) was the primary metabolite in the blood (∼4 mmol/l), with only low concentrations of diglycolic acid (DGA) (∼0.04 mmol/l). In contrast, renal and hepatic concentrations of DGA and of HEAA at 48 h were similar (∼4 mmol/l), indicating a 100-fold concentrative uptake of DGA by kidney tissue. Treatment with fomepizole blocked the formation of HEAA and DGA and the kidney toxicity. Both HEAA and DGA concentrations in the kidney correlated strongly with the degree of kidney damage. Accumulation of HEAA in blood correlated with increased anion gap and decreased blood bicarbonate so appeared responsible for the DEG-induced acidosis. Although these studies suggest that either metabolite may be involved in producing kidney toxicity, the unexpected renal accumulation of DGA at toxic doses of DEG suggests that it must also be considered a possible toxic metabolite of DEG.
二甘醇（DEG）的滥用已导致全球多起流行中毒事件。DEG 通过其代谢产生毒性，尽管其毒性机制尚未进一步确定。本研究旨在探讨血液和靶器官组织中特定代谢物的积累情况，并确定代谢物在组织中的积累与毒性之间的关系。Wistar 大鼠分别给予水、2 g/kg DEG（低剂量）、10 g/kg DEG（高剂量）或 10 g/kg DEG+ 依地酸（15 mg/kg，然后每 12 小时 10 mg/kg，以抑制 DEG 代谢），并在 48 小时内采集血液和组织样本。高剂量 DEG 后，2-羟乙氧基乙酸（HEAA）是血液中的主要代谢物（约 4 mmol/L），而二甘酸（DGA）的浓度较低（约 0.04 mmol/L）。相比之下，肾和肝组织中 DGA 和 HEAA 的浓度在 48 小时时相似（约 4 mmol/L），表明肾组织对 DGA 的浓缩摄取量为 100 倍。依地酸的治疗阻断了 HEAA 和 DGA 的形成和肾毒性。肾损伤程度与肾组织中 HEAA 和 DGA 的浓度密切相关。HEAA 在血液中的积累与阴离子间隙的增加和血液碳酸氢盐的减少相关，表明其可能是 DEG 诱导酸中毒的原因。尽管这些研究表明，HEAA 和 DGA 可能都参与了肾毒性的产生，但在 DEG 的毒性剂量下肾组织中 DGA 的意外积累表明，其也必须被视为 DEG 的一种潜在毒性代谢物。
