Metabolic activation of tris(2,3-dibromopropyl)phosphate to reactive intermediates. I. Covalent binding and reactive metabolite formation in vitro.
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.
Pearson
P G
PG
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Omichinski
J G
JG
McClanahan
R H
RH
Søderlund
E J
EJ
Dybing
E
E
Nelson
S D
SD
D000171:Acrolein / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004247:DNA / Q000378:metabolism; D005411:Flame Retardants / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010755:Organophosphates / Q000378:metabolism / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D005411:Flame Retardants; D010755:Organophosphates; C012085:tris(2,3-dibromopropyl)phosphate; C041548:2-bromoacrolein; C035185:bis(2,3-dibromopropyl)phosphate; D000171:Acrolein; D004247:DNA; D003577:Cytochrome P-450 Enzyme System