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 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. Complete deuterium 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.
Van Beerendonk
G J
GJ
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Pearson
P G
PG
Meijer
D K
DK
Mulder
G J
GJ
Nelson
S D
SD
Meerman
J H
JH
D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003903:Deuterium / Q000009:adverse effects*; D004563:Electrochemistry; D005411:Flame Retardants / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D066298:In Vitro Techniques; D007553:Isotope Labeling; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010755:Organophosphates / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D005411:Flame Retardants; D010755:Organophosphates; C012085:tris(2,3-dibromopropyl)phosphate; D003577:Cytochrome P-450 Enzyme System; D003903:Deuterium; D005982:Glutathione Transferase; D005978:Glutathione