Nephrotoxicity of selectively deuterated and methylated analogues of Tris-BP and Bis-BP in the rat.
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.
Søderlund
E J
EJ
Department of Toxicology, National Institute of Public Health, Oslo 4, Norway.
Omichinski
J G
JG
Dahl
J E
JE
Nelson
S D
SD
Dybing
E
E
D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008745:Methylation; D009336:Necrosis; D009929:Organ Size / Q000187:drug effects; D010755:Organophosphates / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D007555:Isoxazoles; D010755:Organophosphates; D009943:Organophosphorus Compounds; C012085:tris(2,3-dibromopropyl)phosphate; C035185:bis(2,3-dibromopropyl)phosphate; D003404:Creatinine; D005978:Glutathione; C006303:acivicin; D011339:Probenecid