Søderlund E J, Gordon W P, Nelson S D, Omichinski J G, Dybing E
Biochem Pharmacol. 1984 Dec 15;33(24):4017-23. doi: 10.1016/0006-2952(84)90015-7.
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 alpha-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.
磷酸三（2,3-二溴丙基）酯（Tris-BP）被发现可被从未经处理和经苯巴比妥预处理的大鼠获得的肝微粒体代谢。Tris-BP的代谢产物包括溴离子和双（2,3-二溴丙基）磷酸酯（Bis-BP），其形成依赖于NADPH和氧气。与从未经处理的大鼠分离的微粒体相比，从经苯巴比妥预处理的大鼠分离的肝微粒体中这些代谢产物的形成速率显著增加。在存在SKF 525-A或美替拉酮的情况下，溴离子和Bis-BP的形成速率降低，而α-萘黄酮没有影响。各种处理对溴离子释放和Bis-BP形成的影响与先前观察到的Tris-BP激活为诱变和共价结合蛋白代谢产物的情况相似。此外，几种Tris-BP类似物的氧化脱溴速率与其各自的诱变性直接相关。向Tris-BP的微粒体孵育物中添加谷胱甘肽（GSH）使溴离子释放量比对照值大幅增加，但对Bis-BP的形成没有影响。另一方面，向微粒体中添加GSH可降低Tris-BP的共价结合和诱变性，并增加水溶性代谢产物的形成。对大鼠肝微粒体与Tris-BP孵育物的乙酸乙酯提取物进行气相色谱/质谱分析，鉴定出2-溴丙烯醛（2-BA）为代谢产物。在Tris-BP丙基部分的碳原子1处引入氘对溴离子释放或诱变性均无影响，而在碳原子3处标记的类似物对这两种活性均显示出显著的同位素效应。相比之下，在碳原子2处进行氘取代对溴离子释放有显著的同位素效应，但对诱变性没有影响。数据表明，Tris-BP可被大鼠肝微粒体代谢为Bis-BP和2-溴丙烯醛，这一过程由细胞色素P-450催化并释放溴离子。此外，结果与Tris-BP末端碳原子的氧化一致，从而形成2-溴丙烯醛，推测其为主要负责Tris-BP诱变性的代谢产物。
