ISRP trainee Eric Uwimana and colleagues from ISRP Synthesis Core, Project 1 and Project 3 investigated the biotransformation of PCB 91 to OH-PCBs by human liver microsomes (HLMs) Human liver microsomes atropselectively metabolize 2,2',3,4',6-pentachlorobiphenyl (PCB 91) to a 1,2-shift product as the major metabolite. 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.
Uwimana also examined the metabolism of chiral PCBs and the role of several different P450 enzymes found in the human liver. Uwimana first predicted the likely enzymes involved in producing metabolites of four PCB congeners using ADMET Predictor and MetaDrug. He then confirmed the predictions by incubating the four PCBs with the most likely human P450 isoforms. Results demonstrated that chiral PCBs are metabolized in a congener-specific and atropselective manner to OH-PCBs by CYP2A6, CYP2B6, and CYP2E1 in humans.