Role of Tissue Metabolite Accumulation in the Renal Toxicity of Diethylene Glycol

Abstract

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.

Lessons Learned From Yet Another Episode of Diethylene Glycol Poisoning

“…The median serum DGA concentration in the cases was 41 μg/mL, which is almost 10 times higher than that reported to cause nephrotoxicity in the rat model of DEG poisoning. 2,3 Serum HEAA concentrations were significantly higher in cases than in controls. The median serum DGA concentration was more than 14 times higher than that of HEAA.…”

“…Studies from Kenneth McMartin's laboratory at the Louisiana State University Health Sciences Center have demonstrated that contrary to earlier beliefs, DGA, and not HEAA, appears to be the nephrotoxic metabolite, at least in rats. 2 The nephrotoxic potential of DGA appears to derive from its ability to inhibit succinate dehydrogenase, causing mitochondrial dysfunction and consequently reduced energy production in the renal proximal tubule. Whether this same mechanism applies to humans has not been demonstrated.…”

“…2 However, the extended period between exposure and the collection of samples in the Panamanian cases could have allowed HEAA to be oxidized to DGA. In these cases, the median HEAA concentrations were below the detection limit in the urine in both cases and controls.…”

“…Diglycolic acid is concentrated in the kidney. 2 If DEG poisoning is suspected, inhibition of its metabolism by inhibiting alcohol dehydrogenase enzymes is a logical treatment and has been shown to be effective in the rat model. 2 Fomepizole is the preferred antidote for this purpose, although in situations where it is not available ethanol could be used.…”

Cardiotoxicity testing of diglycolic acid using In Vitro and In Vivo models

“…In the absence of published in vivo dose-response and lethal dose (LD)50 data on DGA, we sought out to begin investigating the potential for DGA to engender toxicity. Human in vitro and rat in vivo studies by our group and others have established that DGA is an acute renal and hepatic toxin, with the potential of also being a cardiotoxin [5][6][7][8][9][10]. In a tragic case report of unintentional human DGA oral exposure, not only were the kidneys and liver severely damaged, but there was some evidence of heart injury as well [9].…”