In vitro inhibition of human hepatic and cDNA-expressed sulfotransferase activity with 3-hydroxybenzo[a]pyrene by polychlorobiphenylols.

Sulfonation is a major phase II biotransformation reaction. In this study, we found that several polychlorobiphenylols (OH-PCBs) inhibited the sulfonation of 3-hydroxybenzo[a]pyrene (3-OH-BaP) by human liver cytosol and some cDNA-expressed sulfotransferases. At concentrations > 0.15 microM, 3-OH-BaP inhibited its own sulfonation in cytosol fractions that were genotyped for SULT1A1 variants, as well as with expressed SULT1A11, SULT1A12, and SULT1E1, but not with SULT1A3 or SULT1B1. The inhibition fit a two-substrate kinetic model. We examined the effects of OH-PCBs on the sulfonation of 0.1 or 1.0 microM 3-OH-BaP, noninhibitory and inhibitory substrate concentrations, respectively. At the lower 3-OH-BaP concentration, OH-PCBs with a 3-chloro-4-hydroxy substitution pattern were more potent inhibitors of cytosolic sulfotransferase activity [with concentrations that produced 50% inhibition (IC50) between 0.33 and 1.1 microM] than were OH-PCBs with a 3,5-dichloro-4-hydroxy substitution pattern, which had IC50 values from 1.3 to 6.7 microM. We found similar results with expressed SULT1A11 and SULT1A12. The OH-PCBs were considerably less potent inhibitors when assay tubes contained 1.0 microM 3-OH-BaP. The inhibition mechanism was noncompetitive, and our results suggested that the OH-PCBs competed with 3-OH-BaP at an inhibitory site on the enzyme. The OH-PCBs tested inhibited sulfonation of 3-OH-BaP by SULT1E1, but the order of inhibitory potency was different than for SULT1A1. SULT1E1 inhibitory potency correlated with the dihedral angle of the OH-PCBs. The OH-PCBs tested were generally poor inhibitors of SULT1A3- and SULT1B1-dependent activity with 3-OH-BaP. These findings demonstrate an interaction between potentially toxic hydroxylated metabolites of PCBs and polycyclic aromatic hydrocarbons, which could result in reduced clearance by sulfonation.