Human Liver Microsomes Atropselectively Metabolize 2,2 ',3,4 ',6-Pentachlorobiphenyl (PCB 91) to a 1,2-Shift Product as the Major Metabolite

Polychlorinated biphenlys (PCBs) and their hydroxylated metabolites (OH-PCBs) have been implicated in neurodevelopmental disorders. Several neurotoxic PCBs, such as PCB 91, are chiral because they form stable rotational isomers, or atropisomers, that are nonsuperimposable mirror images of each other. Because only limited information about the metabolism of these PCBs by human cytochrome P450 (P450) enzymes is available, we investigated the biotransformation of PCB 91 to OH-PCBs by human liver microsomes (HLMs). Racemic PCB 91 was incubated with pooled or individual donor HLMs at 37 degrees C, and levels and chiral signatures of PCB 91 and its metabolites were determined. Several OH-PCBs were formed in the order 2,2',4,4',6-pentachlorobiphenyl-3-ol (3-100; 1,2 shift product) > 2,2',3,4',6-pentachlorobiphenyl-5-ol (5-91) >> 2,2',3,4',6-pentachlorobiphenyl-4-ol (4-91) >> 4,5-dihydroxy-2,2',3,4',6-pentachlorobiphenyl (4,5-91). Metabolite formation rates displayed interindividual variability. The first eluting atropisomers of PCB 91, 3-100 and 4-91, and the second eluting atropisomer of 5-91 were enriched in most metabolism studies. The unexpected, preferential formation of a 1,2-shift product and the variability of the OH-PCBs profiles in experiments with individual donor HLMs underline the need for further systematic studies of the atropselective metabolism of PCBs in humans.