Metabolism in vitro of tris(2,3-dibromopropyl)-phosphate: oxidative debromination and bis(2,3-dibromopropyl)phosphate formation as correlates of mutagenicity and covalent protein binding.
Metabolism in vitro of tris(2,3-dibromopropyl)-phosphate: oxidative debromination and bis(2,3-dibromopropyl)phosphate formation as correlates of mutagenicity and covalent protein binding.
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三(2,3-二溴丙基)-磷酸盐的体外代谢：氧化脱溴和双(2,3-二溴丙基)磷酸盐形成与致突变性和共价蛋白结合的相关性。
DOI：
10.1016/0006-2952(84)90015-7
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发表时间：
1984
影响因子：
5.8
通讯作者：
Dybing,E
中科院分区：
文献类型：
--
作者：
Søderlund,EJ;Gordon,WP;Nelson,SD;Omichinski,JG;Dybing,E
三(2，3-二溴丙基)磷酸(Tris-BP)可被未经处理和苯巴比妥预处理的大鼠肝微粒体代谢。Tris-BP的代谢产物包括溴离子和双(2，3-二溴丙基)-磷酸(Bis-BP)，其形成依赖于NADPH和氧气。与未处理的大鼠相比，苯巴比妥预处理的大鼠肝微粒体中这些代谢物的形成速度显著增加。在SKF525-A或甲苯磺隆存在下，溴离子和Bis-BP的生成速率降低，而α-萘黄酮则没有影响。不同处理对溴释放和Bis-BP形成的影响与先前观察到的Tris-BP对诱变和共价蛋白质结合代谢物的激活作用相似。此外，几个Tris-BP类似物的氧化脱溴速率与它们各自的致突变性直接相关。将谷胱甘肽(GSH)加入到Tris-BP的微粒体孵育中，显著增加了溴化物的释放，但对Bis-BP的形成没有影响。另一方面，在微粒体内加入GSH降低了Tris-BP的共价结合和致突变性，增加了水溶性代谢物的形成。大鼠肝微粒体与Tris-BP孵育的乙酸乙酯提取物的GC/MS分析表明，2-溴丙烯醛(2-BA)是一种代谢物。在Tris-BP丙基部分的碳原子序数1处引入氢对溴的释放和致突变性都没有影响，而碳原子3标记的类似物对这两种活性都显示了显著的同位素效应。相反，在碳原子2处的氢取代对溴化物的释放有显著的同位素效应，但对致突变性没有影响。结果表明，Tris-BP可被大鼠肝微粒体代谢成Bis-BP和2-溴代丙烯醛，并在细胞色素P-450的催化下释放出溴离子。此外，结果与Tris-BP末端碳原子的氧化生成2-溴丙烯醛一致，推测2-溴丙烯醛是导致Tris-BP突变的主要代谢物。
Tris(2,3-dibromopropyl)phosphate (Tris-BP) was found to be metabolized by liver microsomes obtained from untreated and phenobarbital-pretreated rats. Metabolites of Tris-BP, whose formation was dependent on NADPH and oxygen, included bromide ion and bis(2,3-dibromopropyl)-phosphate (Bis-BP). The rates of formation of these metabolites were markedly increased in liver microsomes isolated from phenobarbital-pretreated rats compared to microsomes from untreated rats. In the presence of either SKF 525-A or metyrapone, the formation rates of bromide ion and Bis-BP were decreased, whereas α-naphthoflavone had no effect. The effects of the various treatments on bromide release and Bis-BP formation paralleled those that have been previously observed with respect to the activation of Tris-BP to mutagenic and covalently protein bound metabolites. Furthermore, rates of oxidative debromination of several Tris-BP analogs directly correlated with their respective mutagenicities. Addition of glutathione (GSH) to microsomal incubations of Tris-BP increased bromide release substantially over control, values but had no effect on Bis-BP formation. On the other hand, the addition of GSH to microsomes decreased covalent binding and mutagenicity of Tris-BP with increased formation of water soluble metabolites. GC/MS analysis of ethyl acetate extracts from incubations of rat liver microsomes with Tris-BP identified 2-bromoacrolein (2-BA) as a metabolite. Introducing deuterium at the carbon atom number 1 of the propyl moiety of Tris-BP had no effect on either bromide release or mutagenicity, whereas the analog labelled at carbon atom 3 showed significant isotope effects on both activities. In contrast, deuterium substitution at carbon atom 2 gave a significant isotope effect on bromide release, but not on mutagenicity. The data indicate that Tris-BP can be metabolized by rat liver microsomes to Bis-BP and 2-bromoacrolein catalyzed by cytochrome P-450 in a process liberating bromide ions. Further, the results are consistent with oxidation at the terminal carbon atom of Tris-BP thereby forming 2-bromoacrolein, which is postulated to be the metabolite mainly responsible for Tris-BP mutagenicity.