Nephrotoxicity of Selectively Deuterated and Methylated Analogues of Tris‐BP and Bis‐BP in the Rat

Abstract

Selectively deuterated and methylated analogues of the flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) and its nephrotoxic metabolite bis(2,3-dibromopropyl)phosphate (Bis-BP) were compared to Tris-BP and Bis-BP in inducing acute renal damage in rats. None of the deuterated Tris-BP or Bis-BP analogues significantly altered morphological evidence of nephrotoxicity compared to the protio compounds. On the other hand, some of the selectively methylated analogues were much less nephrotoxic. Although the C1-methyl analogues of both Tris-BP and Bis-BP were as potent nephrotoxicants as Tris-BP and Bis-BP, respectively, neither the C2-methyl nor the C3-methyl analogues were significantly nephrotoxic. Interestingly, whereas the 3,4-dibromobutyl homologue of Tris-BP was not nephrotoxic, the corresponding 3,4-dibromobutyl-Bis homologue was as nephrotoxic as Bis-BP. Additional investigations with treatments that are known to decrease nephrotoxicity caused by several halogenated alkenes, showed that L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) and aminooxyacetic acid were without effects on Tris-BP induced renal damage. Probenecid pretreatment led to a reduction in Tris-BP and Bis-BP tubular necrosis, these effects may be related to inhibition of Bis-BP uptake in the kidney. It appears that the cysteine conjugate beta-lyase pathway is not involved in the generation of nephrotoxic metabolites of Tris-BP.