Deuterium Isotope Effect on the Metabolism of the Flame Retardant Tris(2,3-dibromopropyl) Phosphate in the Isolated Perfused Rat Liver

The metabolism of tris(2,3-dibromopropyl) phosphate (Tris-BP)was compared with that of completely deuterated Tris-BP (D15-Tris-BP)in an isolated, recirculating rat liver perfusion system inorder to determine the relative quantitative importance of twodifferent biotransformation pathways of Tris-BP: (i) cytochromeP450-mediated metabolism and (ii) GSH S-transferase-mediatedmetabolism. To accomplish this we quantitated the biliary excretionof S-(3-hydroxypropyl)glutathione (GSOH) as a marker metabolitefor cytochrome P450-mediated metabolism and that of S-(2,3-dihydroxypropyl)glutathione (GSOHOH) as a marker metabolite for GSH S-transferase-mediatedmetabolism. Completedeuterium substitution of Tris-BP significantlydecreased the formation of GSOH, whereas there was no effecton the formation of GSOHOH. Because our previous studies showeda large decrease in genotoxicity of D15-Tris-BP compared toTris-BP, the present results support our hypothesis that cytochromeP450-mediated metabolism is responsible for the genotoxic effectsof Tris BP in the rat liver.