Enantioselective Formation of Methyl Sulfone Metabolites of 2,2‘,3,3‘,4,6‘-Hexachlorobiphenyl in Rat

Abstract

Several nonsymmetric polychlorinated biphenyl (PCB) congeners form atropisomers due to steric hindrance of free rotation around the phenyl-phenyl bond. It is evident from the literature that both chiral PCB congeners and their atropisomeric methylsulfonyl-PCB metabolites, formed in higher animals and in humans, are present in biota as nonracemic mixtures. Chiral methylsulfonyl-PCBs are strongly dominated by one of the atropisomers in mammalian tissues. The aim of the present study is to examine enantioselective metabolism, retention, and excretion of 2,2',3,3',4,6'-hexachlorobiphenyl (CB-132) in rat by administration of a CB-132 racemate and pure atropisomers. Chemical analysis of liver, lung, and adipose tissue from the rats showed a strong retention of one of the CB-132 atropisomers and a similar, but even more pronounced, accumulation of one of the atropisomers of the meta- and para-methylsulfonyl-substituted CB-132 metabolites in these tissues. Metabolites with R structures were predominately formed from one of the atropisomers of CB-132. The slower metabolism of the other atropisomer of CB-132 and its pronounced excretion in feces suggest an enantioselective metabolism. The results indicate enantio-selective formation of the methylsulfonyl-CB132 metabolites and confirm the critical role of stereochemistry of chemicals for their metabolism.