In vitro and in vivo covalent binding of the kidney toxicant and carcinogen tris(2,3-dibromopropyl)-phosphate.
The nephrotoxicant and nephrocarcinogen tris(2,3-dibromopropyl)-phosphate (Tris-BP) is activated to products which bind covalently to microsomal protein by a cytochrome P-450 dependent oxidation reaction. Binding to rat liver microsomes proceeds 15 times faster than with kidney microsomes. The binding in liver microsomes is markedly increased by phenobarbital pretreatment, the apparent Vmax of the reaction is 175 pmol/mg microsomal protein/min with control microsomes and 1053 pmol/mg protein/min with induced microsomes. Binding with kidney microsomes is doubled after pretreatment with polychlorinated biphenyls. 2,3-Dibromopropanol (2,3-DBP), a hydrolysis product of Tris-BP, is also activated to covalently protein-bound products, but at a much slower rate than Tris-BP. Administration of Tris-BP to rats leads to its covalent binding to proteins in liver and kidney, with 5 time higher binding levels in kidney than in liver, correlating with its relative organotoxic potential in single dose experiments. Binding to proteins in the kidney was increased by pretreatment of animals with polychlorinated biphenyls. A covalent interaction of Tris-BP could also be demonstrated to DNA, both when DNA was added to liver microsomal incubations in vitro and to DNA extracted from liver and kidney after administration of Tris-BP in vivo. The binding levels were 4 times higher to kidney DNA than to liver DNA.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D010755:Organophosphates / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D002273:Carcinogens; D010755:Organophosphates; D009943:Organophosphorus Compounds; C012085:tris(2,3-dibromopropyl)phosphate; D004247:DNA; D003577:Cytochrome P-450 Enzyme System