METABOLISM AND TOXICITY OF HALOGENATED ALKYL PHOSPHATES

拟议研究的总体目标是确定这些 卤代烷基化合物的结构特征使它们 高毒性或相对无毒。 为此， 磷酸三（2，3-二溴丙基）酯（Tris-BP）的代谢活化和 结构上相关的化合物将被检查关于他们的 遗传毒性和细胞毒性作用。 特别是氘代和放射性标记 Tris-BP的类似物将被用于探索肾毒性的机制 在大鼠体内以及在制备 从大鼠分离的肾细胞。 Tris-BP的立体异构体将是 合成以确定是否相邻的相对构型 烷基溴是致突变性的决定因素。 2-溴丙烯醛，一种主要的 Tris-BP和其他卤代化合物的致突变代谢物，将被 与核苷和谷胱甘肽反应，以研究 与DNA或蛋白质的加合物，可能导致结构损伤。 性腺 Tris-BP的毒性作用将与 三（1，3-二氯-2-丙基）磷酸盐（Tris-CP）在小鼠中的试验 异常精子 这是重要的，因为Tris-CP已经在 男大学生的精液 最后，特别是1，2-二溴-3-氯丙烷的氘代类似物 （DBCP）将被合成，以研究这种激活的机制。 杀线虫剂到诱变产品。 DBCP在结构上与 卤化烷基磷酸酯和几种合成男性抗生育剂 药物，并引起类似的遗传毒性和细胞毒性作用。 结果 这些研究应提供更有力的依据， 卤化烷基磷酸盐和其他卤化 在结构上相关的化合物。

The overall objective of the proposed research is to determine those structural features of halogenated alkyl compounds which render them either highly toxic or relatively non-toxic. To this end the mechanisms of metabolic activation of tris(2,3-dibromoprpyl)phosphate (Tris-BP) and structurally related compounds will be examined with regard to their genotoxic and cytotoxic effect. Specifically deuterated and radiolabeled analogs of Tris-BP will be used to probe the mechanism of nephrotoxicity caused by this brominated alkyl phosphate in rats and in preparations of isolated kidney cells from rats. Stereoisomers of Tris-BP will be synthesized to determine if the relative configuration of the adjacent alkyl bromines is a determinant of mutagenicity. 2-Bromoacrolein, a major mutagenic metabolite of Tris-BP and other halogenated compounds, will be reacted with nucleosides and glutathione to investigate the nature of adducts with DNA or protein that may cause structural damage. Gonadal toxic effects of Tris-BP will be compared to those of tris(1,3-dichloro-2-propyl) phosphate (Tris-CP) in mice using an assay for abnormal sperm. This is important inasmuch as Tris-CP has been detected in the semen of male college students. Finally, specifically deuterated analogs of 1,2-dibromo-3-chloropropane (DBCP) will be synthesized to investigate mechanisms for activation of this nematocide to mutagenic products. DBCP is structurally related to the halogenated alkyl phosphates and several synthetic male antifertility agents, and it causes similar genotoxic and cytotoxic effects. Results of these studies should provide a stronger basis for making benefit/risk assessments for halogenated alkyl phosphates and other halogenated compounds that are related in structure.