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Metabolic Activation of Tris(2,3-dibromopropyl)phosphate to Reactive Intermediates. I. Covalent Binding and Reactive Metabolite Formation in Vitro

1993; Elsevier BV; Volume: 118; Issue: 2 Linguagem: Inglês

10.1006/taap.1993.1024

1096-0333

Paul G. Pearson, James G. Omichinski, Robert H. McClanahan, Erik J. Søderlund, Erik Dybing, S D Nelson,

Carcinogens and Genotoxicity Assessment

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 15-20× 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 H218O 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 α-bromoketone metabolite of Tris-BP that can either alkylate proteins directly or be hydrolyzed to His-HP and an α-bromo-α′-hydroxyketone that can alkylate microsomal proteins.