Mono-hydroxylated polychlorinated biphenyls are potent aryl hydrocarbon receptor ligands in recombinant yeast cells

The toxicities of polychlorinated biphenyls (PCBs) are thought to be mediated mainly by the aryl hydrocarbon receptor (AhR). However, little is known about changes to AhR-mediated effects caused by metabolic conversion of PCBs. To investigate whether hydroxylation affects the affinity of PCBs for the AhR, we measured the AhR agonistic activity of mono-hydroxylated PCBs (mono-OH-PCBs) and their non-hydroxylated analogs (PCBs) using yeast cells transduced with the human AhR and its response pathway. Fifty-two of 84 tested OH-PCBs and 12 of 24 PCBs exhibited AhR agonistic effects. Of 49 OH-PCBs that had the same chlorination patterns as the tested PCBs, 26 had activities that were more than twice those of their analogous PCBs, or became activated if their non-hydroxylated analogs were inactive. In particular, 3′,4,5′-trichlorobiphenyl-2-ol and 3′,4,4′-trichlorobiphenyl-3-ol were 37- and 22-fold more potent than their non-hydroxylated analogs and were 1.42 times and 1.08 times, respectively, as active as a standard, β-naphthoflavone. The activities of only 5 OH-PCBs were reduced to less than half those of their non-hydroxylated counterparts. No tested PCBs were inactivated by the presence of a hydroxyl group. These findings underscore the need to rethink the toxicological evaluation of hydroxylated metabolites of PCBs and their abundance in the environment.