Homing in on the Toxicity of Diethylene Glycol
Seventy-four years after the US Elixir of Sulfanilamide tragedy, we’re still trying to figure out exactly how diethylene glycol (DEG) damages the kidneys. And 74 years later, we are, in fact, closer to understanding the solvent’s toxicity, thanks to continuing investigative work at the Louisiana State University Health Sciences Center in Shreveport. In July and August, researchers from the Department of Pharmacology, Toxicology, and Neuroscience published important sequential studies on DEG toxicity (for access to these articles, go to Besenhofer et al and Landry et al).
What has been known is that DEG becomes toxic after it is metabolized to 2-hydroxyethyoxyacetic acid (HEAA) and diglycolic acid (DGA) and that fomepizole, a DEG antidote, inhibits this metabolism. HEAA has generally been fingered as the primary toxicant of DEG poisoning and the cause of associated kidney dysfunction. But a new animal study and in-vitro work suggest that DGA is an important instigator of renal failure (specifically proximal tubular necrosis) in DEG poisoning.
By administering various doses of DEG, with or without fomepizole, to Wister rats, Besenhofer et al determined that the primary DEG metabolite in blood is HEAA after high DEG doses, and that HEAA is probably responsible for the anion gap and low bicarbonate levels seen in DEG poisoning. However, concentrations of HEAA and DGA were similar in renal and hepatic tissues of rats at 48 hours, with a 100-fold “concentrative uptake of DGA” by the kidney. Renal concentrations of both HEAA and DGA correlated with kidney damage, indicating that DGA (as well as HEAA) is a significant contributor to renal injury in DEG poisoning (at least in rats). Importantly fomepizole blocked the formation of both HEAA and DGA, thereby inhibiting renal toxicity.
These animal data are supported by an in-vitro experiment from Landry et al, who incubated human proximal tubule cells with DEG, HEAA, and/or DGA in culture. What the researchers found, to their relative surprise, was that the DEG metabolite HEAA did not produce cell death. However, DGA produced dose-dependent cell necrosis. And on the basis of additional experiments, Landry et al suggested that DGA uptake and its renal accumulation is probably mediated by a cell-based transporter mechanism.
A native East Tennessean, Barbara Martin is a formerly practicing, board-certified neurologist who received her BS (psychology, summa cum laude) and MD from Duke University before completing her postgraduate training (internship, residency, fellowship) at the Hospital of the University of Pennsylvania in Philadelphia. She has worked in academia, private practice, medical publishing, drug market research, and continuing medical education (CME). For the last 3 years, she has worked in a freelance capacity as a medical writer, analyst, and consultant. Follow Dr. Barbara Martin on Google + and Twitter.
