Diglycolic acid inhibits succinate dehydrogenase activity in human proximal tubule cells leading to mitochondrial dysfunction and cell death

Landry, Greg M.; Dunning, Cody; Conrad, Taylor; Hitt, Mallory J.; McMartin, Kenneth E.

doi:10.1016/j.toxlet.2013.06.231

Cited by 36 publications

(12 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Whether the correlation between cytotoxicity and increased ROS levels is causative remains to be fully investigated. Reports by Landry et al [23] and Conrad et al [30] show that the reduction of DGA-induced ROS by antioxidants does not prevent mitochondria from becoming dysfunctional, suggesting that ROS elevations may simply be a secondary effect. The third major finding of our study was that DGA cytotoxicity elicited strong KIM-1 expression.…”

Section: Discussionmentioning

confidence: 98%

Comparison of diglycolic acid exposure to human proximal tubule cells in vitro and rat kidneys in vivo

et al. 2017

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 98%

Comparison of diglycolic acid exposure to human proximal tubule cells in vitro and rat kidneys in vivo

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Previous studies have suggested that the nephrotoxic metabolite of DEG is DGA, which leads in vitro to ATP depletion, reactive oxygen species production, succinate dehydrogenase inhibition, and ultimately necrotic proximal tubule cell death (Landry et al, 2011, 2013). Also, DGA is markedly accumulated in liver and kidney, as compared to the plasma DGA levels, of DEG-intoxicated rats (Besenhofer et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Severe glycogen depletion has also been reported in livers of animals administered GSH-depleting agents, where the GSH deficiency induces glycogen breakdown by effectively altering the GSH/GSSG ratio to then stimulate glycogenolysis (Braun et al, 1996). It is likely that the severe glycogen depletion seen in animals administered 10 g/kg DEG is a result of marked GSH depletion related to the capability of DGA to induce significant increases in reactive oxygen species leading to marked alterations in cellular redox status (Landry et al, 2013). The increased glycogenolysis and subsequent glycogen breakdown would be expected to mobilize glucose, thereby increasing circulating blood glucose levels.…”

Section: Discussionmentioning

confidence: 99%

Diethylene glycol-induced toxicities show marked threshold dose response in rats

Landry

Dunning

Abreo

et al. 2015

Toxicology and Applied Pharmacology

Self Cite

View full text Add to dashboard Cite

Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments.

show abstract

“…Some of these alcohols are summarized briefly in Figure 2. Other than ethanol and isopropanol, HD and fomepizole are commonly used to treat these poisonings (38)(39)(40).…”

Section: Other Toxic Alcoholsmentioning

confidence: 99%

Extracorporeal Removal of Poisons and Toxins

King

Kern

Jaar

2019

CJASN

View full text Add to dashboard Cite

Extracorporeal therapies have been used to remove toxins from the body for over 50 years and have a greater role than ever before in the treatment of poisonings. Improvements in technology have resulted in increased efficacy of removing drugs and other toxins with hemodialysis, and newer extracorporeal therapy modalities have expanded the role of extracorporeal supportive care of poisoned patients. However, despite these changes, for at least the past three decades the most frequently dialyzed poisons remain salicylates, toxic alcohols, and lithium; in addition, the extracorporeal treatment of choice for therapeutic removal of nearly all poisonings remains intermittent hemodialysis. For the clinician, consideration of extracorporeal therapy in the treatment of a poisoning depends upon the characteristics of toxins amenable to extracorporeal removal (e.g., molecular mass, volume of distribution, protein binding), choice of extracorporeal treatment modality for a given poisoning, and when the benefit of the procedure justifies additive risk. Given the relative rarity of poisonings treated with extracorporeal therapies, the level of evidence for extracorporeal treatment of poisoning is not robust; however, extracorporeal treatment of a number of individual toxins have been systematically reviewed within the current decade by the Extracorporeal Treatment in Poisoning workgroup, which has published treatment recommendations with an improved evidence base. Some of these recommendations are discussed, as well as management of a small number of relevant poisonings where extracorporeal therapy use may be considered.

show abstract

Diglycolic acid inhibits succinate dehydrogenase activity in human proximal tubule cells leading to mitochondrial dysfunction and cell death

Cited by 36 publications

References 28 publications

Comparison of diglycolic acid exposure to human proximal tubule cells in vitro and rat kidneys in vivo

Comparison of diglycolic acid exposure to human proximal tubule cells in vitro and rat kidneys in vivo

Diethylene glycol-induced toxicities show marked threshold dose response in rats

Extracorporeal Removal of Poisons and Toxins

Contact Info

Product

Resources

About