Metabolic activation of tris(2,3-dibromopropyl)phosphate to reactive intermediates. I. Covalent binding and reactive metabolite formation in vitro

• Published in: Toxicology and applied pharmacology Vol. 118; no. 2; p. 186
• Main Authors: Pearson, P G, Omichinski, J G, McClanahan, R H, Søderlund, E J, Dybing, E, Nelson, S D
• Format: Journal Article
• Language: English
• Published: United States 01-02-1993
• Subjects: Acrolein - analogs & derivatives; Acrolein - metabolism; Animals; Biotransformation; Cytochrome P-450 Enzyme System - physiology; DNA - metabolism; Flame Retardants - pharmacokinetics; In Vitro Techniques; Male; Microsomes, Liver - metabolism; Organophosphates - metabolism; Organophosphates - pharmacokinetics; Oxidation-Reduction; Protein Binding; Rats; Rats, Sprague-Dawley
• ISSN: 0041-008X
• DOI: 10.1006/taap.1993.1024

Analogs of tris(2,3-dibromopropyl)phosphate (Tris-BP) either labeled at specific positions with carbon-14, phosphorus-32, or oxygen-18 or dual-labeled with both deuterium and tritium were used as metabolic probes to study the chemical and metabolic events in the bioactivation of Tris-BP to chemically reactive metabolites in liver microsomal preparations. Oxidation at the terminal (C-3) carbon atom of the propyl groups of Tris-BP yielded the direct-acting mutagen 2-bromoacrolein as the major metabolite that binds to DNA. Although this reactive metabolite also appears to bind to microsomal protein, the rate of binding of radiolabeled Tris-BP to protein is 15-20x greater than binding to DNA, and some metabolites that retain the phosphate group are bound. Studies with deuterated analogs of Tris-BP implicate oxidation at C-2 of the propyl group as a major pathway that leads to protein binding which is enhanced by phenobarbital pretreatment of rats. Moreover, investigations with 18O-Tris-BP and H2(18)O show that Bis-BP that is formed from oxidation of Tris-BP incorporates one atom of oxygen from water. Deuterium isotope studies suggest that most of the Bis-BP arises from initial oxidation at C-2. Taken together these studies indicate that P-450 oxidation of Tris-BP at C-2 of the propyl group yields a reactive alpha-bromoketone metabolite of Tris-BP that can either alkylate proteins directly or be hydrolyzed to Bis-BP and an alpha-bromo-alpha'-hydroxyketone that can alkylate microsomal proteins.