Pearson P G, Omichinski J G, McClanahan R H, Søderlund E J, Dybing E, Nelson S D
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Toxicol Appl Pharmacol. 1993 Feb;118(2):186-95. 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.
三（2,3-二溴丙基）磷酸酯（Tris-BP）的类似物，要么用碳-14、磷-32或氧-18在特定位置进行标记，要么同时用氘和氚进行双标记，被用作代谢探针，以研究在肝微粒体制剂中Tris-BP生物活化成化学反应性代谢物的化学和代谢过程。Tris-BP丙基末端（C-3）碳原子的氧化产生了直接作用的诱变剂2-溴丙烯醛，作为与DNA结合的主要代谢物。尽管这种反应性代谢物似乎也与微粒体蛋白结合，但放射性标记的Tris-BP与蛋白的结合速率比与DNA的结合速率大15-20倍，并且一些保留磷酸基团的代谢物也会结合。对Tris-BP氘代类似物的研究表明，丙基C-2位的氧化是导致蛋白结合的主要途径，大鼠经苯巴比妥预处理后这种结合会增强。此外，用18O-Tris-BP和H2(18)O进行的研究表明，由Tris-BP氧化形成的双（2,3-二溴丙基）磷酸酯（Bis-BP）从水中掺入了一个氧原子。氘同位素研究表明，大部分Bis-BP来自C-2位的初始氧化。综合这些研究表明，Tris-BP在丙基C-2位的P-450氧化产生了一种反应性的α-溴代酮代谢物，该代谢物可以直接使蛋白烷基化，或者水解成Bis-BP和一种可以使微粒体蛋白烷基化的α-溴-α'-羟基酮。
