Abstract
PCBs and their hydroxylated metabolites have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB developmental neurotoxicity; however, only limited information is available regarding the metabolism of these congeners in humans. We hypothesize that the oxidation of 2,2′,3,3′,4,6′-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) is atropselective and displays inter-individual variability. To test this hypothesis, PCB 132 (50 μM) was incubated with pooled or single donor HLMs for 10, 30 or 120 min at 37 °C, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite formed by different HLM preparations was either 2,2′,3,4,4′,6′-hexachlorobiphenyl-3′-ol (3′-140) or 2,2′,3,3′,4,6′-hexachlorobiphenyl-5′-ol (5′-132). 2,2′,3,3′,4,6′-Hexachlorobiphenyl-4′-ol (4′-132) and 2,2′,3,3′,4,6′-hexachlorobiphenyl-4′,5′-diol (4′,5′-132) were minor metabolites. The second eluting atropisomer of PCB 132 was slightly enriched in some HLM incubations. The formation of the first eluting atropisomer of 3′-140 was nearly enantiospecific (EF > 0.8). The second eluting atropisomer of 5′-132 was enriched in all microsomal preparations investigated. EF values differed slightly between single donor HLM preparations (EF = 0.84 to 0.96 for 3′-140; EF = 0.12 to 0.19 for 5′-132). These findings suggest that there are inter-individual differences in the atropselective biotransformation of PCB 132 to OH-PCBs in humans that may affect neurotoxic outcomes.