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© 1995 Oxford University Press

research-article

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

GEERTJE J. M. VAN BEERENDONK*, PAUL G. PEARSON{dagger}, DIRK K. F. MEIJER{ddagger}, GERARD J. MULDER*, SIDNEY D. NELSON§ and JOHN H. N. MEERMAN*,1

*Divisjon of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University Leiden, The Netherlands {dagger}Drug Metabolism Research, Upjohn Laboratories, Kalamazoo Kalamazoo, Michigan 49001 {ddagger}Department of Pharmacology and Therapeutics, University Center for Pharmacy, University of Groningen Groningen, The Netherlands §Department of Medicinal Chemistry University of Washington Seattle, Washington 98195

Received June 13, 1994; accepted May 2, 1995

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 in order to determine the relative quantitative importance of two different biotransformation pathways of Tris-BP: (i) cytochrome P450-mediated metabolism and (ii) GSH S-transferase-mediated metabolism. To accomplish this we quantitated the biliary excretion of S-(3-hydroxypropyl)glutathione (GSOH) as a marker metabolite for cytochrome P450-mediated metabolism and that of S-(2,3-dihydroxypropyl) glutathione (GSOHOH) as a marker metabolite for GSH S-transferase-mediated metabolism. Completedeuterium substitution of Tris-BP significantly decreased the formation of GSOH, whereas there was no effect on the formation of GSOHOH. Because our previous studies showed a large decrease in genotoxicity of D15-Tris-BP compared to Tris-BP, the present results support our hypothesis that cytochrome P450-mediated metabolism is responsible for the genotoxic effects of Tris BP in the rat liver.


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