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 comp ared with that of completely deuterated Tris-BP (D15-Tris-BP) in an is olated, recirculating rat liver perfusion system in order to determine the relative quantitative importance of two different biotransformati on pathways of Tris-BP: (i) cytochrome P450-mediated metabolism and (i i) GSH S-transferase-mediated metabolism. To accomplish this we quanti tated the biliary excretion of S-(3-hydroxypropyl)glutathione (GSOH) a s a marker metabolite for cytochrome P450-mediated metabolism and that of S-(2,3-dihydroxypropyl) glutathione (GSOHOH) as a marker metabolit e for GSH S-transferase-mediated metabolism. Complete deuterium substi tution of Tris-BP significantly decreased the formation of GSOH, where as there was no effect on the formation of GSOHOH. Because our previou s studies showed a large decrease in genotoxicity of D15-Tris-BP compa red to Tris-BP, the present results support our hypothesis that cytoch rome P450-mediated metabolism is responsible for the genotoxic effects of Tris-BP in the rat liver. (C) 1995 Society of Toxicology