METABOLISM AND TOXICITY OF HALOGENATED ALKYL PHOSPHATES

卤代烷基化合物被广泛用作除草剂， 杀虫剂和阻燃剂，许多被用作 制造过程中的中间体。其中的几个 已发现化合物具有遗传毒性和细胞毒性。这个 拟议研究的总体目标是确定 卤代烷基化合物的结构特征 遗传毒性和急性细胞毒性的重要决定因素， 并了解卤代烷基化合物如何与 组织成分会造成毒性。 具体来说，阻燃剂的毒性机理 化学品三(2，3-二溴丙基)磷酸(Tris-BP)和三(1，3-二溴丙基)磷酸 二氯丙基)磷酸(Tris-CP)，以及杀线虫剂1，2- 将对二溴-3-氯丙烷(DBCP)进行研究。 肾脏毒性的机制将通过治疗大鼠来研究 已知的调节肾脏细胞色素P-450的药物 和谷胱甘肽浓度，以确定它们在中毒或 卤代化合物的解毒途径。两者都有 分离的肾脏细胞和睾丸细胞将被用来阐明 急性毒性和遗传毒性机制的研究进展 这些目标细胞群中的卤代化合物。细胞 膜损伤将通过细胞存活率(台盼蓝)进行评估 排除)和酶(LDH)泄漏，以及DNA损伤 DNA的碱性洗脱。代谢物将用高效液相色谱法进行分离 并用软电离质谱仪确定了它们的结构 技术(FAB MS/MS)。选择性的氢化和甲基化 Tris-BP、Tris-CP和DBCP的类似物显著减少 有毒物质将与它们的母体化合物进行比较以确定 结构修饰如何改变毒性和新陈代谢。 最后，对Tris-BP、Tris-BP、Tris-BP突变代谢物的结构进行了研究。 CP和DBCP将由以下两个特性确定 通过与合成标准进行比较， 只要是可行的，就会采取行动。如果确定了诱变剂，它们将被 与核苷反应，与DNA加合物进行比较。 这些研究将与正在进行的研究平行进行 表征2-溴代丙烯醛与DNA的反应。2- 溴丙烯醛已被认为是一种强有力的直接作用 Tris-BP和DBCP的致突变代谢产物。

Halogenated alkyl compounds are used extensively as herbicides, pesticides, and fire retardants, and many are employed as intermediates in manufacturing processes. Several of these compounds have been found to be genotoxic and cytotoxic. The overall objectives of the proposed research are to determine those structural features of halogenated alkyl compounds that are important determinants of genotoxicity and acute cytotoxicity, and to understand how halogenated alkyl compounds interact with tissue components to cause toxicity. Specifically, the mechanisms of toxicity of the flame retardant chemicals tris(2,3-dibromopropyl)phosphate (Tris-BP) and tris(1,3- dichloropropyl)phosphate (Tris-CP), and of the nematocide, 1,2- dibromo-3-chloropropane (DBCP), will be investigated. Mechanisms of kidney toxicity will be examined by treating rats will agents that are known to modulate renal cytochromes P-450 and GSH concentrations to determine their role in toxication or detoxication pathways of the halogenated compounds. Both isolated kidney cells and testicular cells will be used to elucidate mechanisms of acute toxicity and genotoxicity caused by the halogenated compounds in these target cell populations. Cell membrane damage will be assessed by cell viability (trypan blue exclusion) and enzyme (LDH) leakage, and DNA damage by alkaline elution of DNA. Metabolites will be isolated by HPLC and their structures elucidated by soft ionization mass spectral techniques (FAB MS/MS). Selectively deuterated and methylated analogs of Tris-BP, Tris-CP, and DBCP that are significantly less toxic will be compared with their parent compounds to determine how the structural modifications altered toxicity and metabolism. Finally, the structures of mutagenic metabolites of Tris-BP, Tris- CP and DBCP will be determined both by characterization of trapped derivatives and by comparison with synthetic standards, whenever it is feasible. If mutagens are identified, they will be reacted with nucleosides for comparisons with DNA adducts. These studies will parallel studies that are ongoing to characterize the reactions of 2-bromoacrolein with DNA. 2- Bromoacrolein has been identified as a potent direct-acting mutagenic metabolite of Tris-BP and DBCP.