Stereoselective Metabolism of a b and g Hexabromocyclododecanes (HBCDs) by Human Liver Microsomes and CYP3A4.
This is the first study investigating the in vitro metabolism of a b and g hexabromocyclododecane (HBCD) stereoisomers in humans and providing semiquantitative metabolism data. Human liver microsomes were incubated with individual racemic mixtures and with individual stereoisomers of a b and g HBCDs, the hydroxylated metabolites formed were analyzed by liquid chromatography tandem mass spectrometry, and the value of the intrinsic in vitro clearance (Clint,vitro) was calculated. Several mono and dihydroxylated metabolites of a b and g HBCDs were formed, with mono OH HBCDs being the major metabolites. No stereoisomerization of any of the six a b and g HBCD isomers catalyzed by cytochrome P450 (CYP) enzymes occurred. The value of Clint,vitro of a HBCDs was significantly lower than that of b HBCDs, which, in turn, was significantly lower than that of g HBCDs (p 0.05) Such differences were explained by the significantly lower values of Clint,vitro of each a HBCD stereoisomer than those of the b and g HBCD stereoisomers. In addition, significantly lower values of Clint,vitro of the over the )a and b HBCD stereoisomers, but not g HBCDs, were obtained. Our data offer a possible explanation of the enrichment of a HBCDs over b and g HBCDs on the one hand and, on the other hand, of )a HBCDs over )a HBCDs previously reported in human samples. It also offers information about the mechanism resulting in such enrichments, the stereoisomer selective metabolism of a b and g HBCDs catalyzed by CYPs with the lack of stereoisomerization.
Environmental science technology