The relative toxicity of brodifacoum enantiomers. (15th May 2019)

• Record Type: Journal Article
• Authors: Feinstein, Douglas L.; Gierzal, Kamil; Iqbal, Asif; Kalinin, Sergey; Ripper, Richard; Lindeblad, Matthew; Zahkarov, Alexander; Lyubimov, Alexander; van Breemen, Richard; Weinberg, Guy; Rubinstein, Israel
• Is Part Of: Toxicology letters. Volume 306(2019)
• Page Start: 61
• Page End: 65
• Publication Date: 2019-05-15
• Subjects: Superwarfarins -- Brodifacoum -- Enantiomer -- Diastereomer -- Anticoagulation; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.02.011
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: The long acting anti-coagulant brodifacoum has 4 isomers, however their relative toxicities are not known. HPLC was used to obtain 2 pairs of BDF diastereomers. In adult male rats BDF-cis diastereomers are more toxic than the BDF-trans forms. BDF-cis has a longer half-life than BDF-trans, which could contribute to increased toxicity. Abstract: Brodifacoum (BDF) is a potent, long-acting anticoagulant rodenticide that can cause fatal poisoning in humans. The chemical structure of BDF includes 2 chiral carbons, resulting in 2 pairs of diastereomers, BDF-cis (R/S and S/R) and BDF-trans (R/R and S/S). However, the relative potency of these molecules is not known. The purpose of this study was to compare the in vitro and in vivo toxic effects of the 2 BDF diastereomer pairs. In adult Sprague-Dawley rats BDF-cis was significantly more toxic than BDF-trans (LD50 values of 219 versus 316 μg/kg, respectively) while racemic BDF had intermediate potency (266 μg/kg). In adult New Zealand white rabbits, BDF-cis had a longer half-life than BDF-trans which could contribute to its observed increased toxicity. Lastly, BDF-cis (10 μM), but not BDF-trans, damaged cultured SH-SY5Y human neuroblastoma cells by attenuating mitochondrial reductive capacity. Taken together, these data suggest that different toxic manifestations of BDF poisoning in mammals could be attributed, in part, to differences in relative enantiomer concentrations present in racemic formulations of this commercially-available toxicant.