Mutagenic Activation of Tris(2,3‐dibromopropyl)phosphate: The Role of Microsomal Oxidative Metabolism

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Abstract
The flame retardant trist(2,3-dibromopropyl)phosphate (Tris-BP) is converted to products which are mutagenic for Salmonella typhimurium TA 100 in the presence of rat liver microsomes, NADPH and O2. Other mutagenic bromopropyl-compounds included 2,3-dibromopropene and 2,3-dibromopropionic acid, which were directly mutagenic, and 2,3-dibromopropanol and tris(2-bromopropyl)phosphate which were weakly mutagenic after addition of liver microsomes and cofactors. Typical in vivo and in vitro inhibitors of cytochrome P-450 inhibited Tris-BP mutagenicity. The effects of inducers of cytochrome P-450 on Tris-BP mutagenicity was dependent on the concentration of mutagen and microsomal protein in the assay, indicating complexity in the kinetics involved when dealing with possible multiple pathways that lead to mutagenicity. Addition of glutathione strongly inhibited Tris-BP mutagenicity. Tris-BP is apparently oxidized to a reactive electrophile, possibly the 2-keto derivative, which could react with nucleophilic groups in DNA and lead to mutation.