Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes and Its Implications for PCB 132 Neurotoxicity

Abstract

<jats:title>Abstract</jats:title> <jats:p>Polychlorinated biphenyls (PCBs) have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB neurotoxicity. Only limited information is available regarding the atropselective metabolism of these congeners in humans and their atropselective effects on neurotoxic outcomes. Here we investigate the hypothesis that the oxidation of 2,2′,3,3′,4,6′-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) and their effects on dopaminergic cells in culture are atropselective. Racemic PCB 132 was incubated with pooled or single donor HLMs, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite was either 2,2′,3,4,4′,6′-hexachlorobiphenyl-3′-ol (3′-140), a 1,2-shift product, or 2,2′,3,3′,4,6′-hexachlorobiphenyl-5′-ol (5′-132). The PCB 132 metabolite profiles displayed interindividual differences and depended on the PCB 132 atropisomer. Computational studies suggested that 3′-140 is formed via a 3,4-arene oxide intermediate. The second eluting atropisomer of PCB 132, first eluting atropisomer of 3′-140, and second eluting atropisomer of 5′-132 were enriched in all HLM incubations. Enantiomeric fractions of the PCB 132 metabolites differed only slightly between the single donor HLM preparations investigated. Reactive oxygen species and levels of dopamine and its metabolites were not significantly altered after a 24 h exposure of dopaminergic cells to pure PCB 132 atropisomers. These findings suggest that there are interindividual differences in the atropselective biotransformation of PCB 132 to its metabolites in humans; however, the resulting atropisomeric enrichment of PCB 132 is unlikely to affect neurotoxic outcomes associated with the endpoints investigated in the study.</jats:p>

Characterization of the Metabolic Pathways of 4-Chlorobiphenyl (PCB3) in HepG2 Cells Using the Metabolite Profiles of Its Hydroxylated Metabolites

“…The observation that PCB3 is oxidized in the meta or para position is consistent with studies demonstrating that higher chlorinated PCBs are preferentially oxidized in meta and para positions in studies with recombinant human cytochrome P450 enzymes or human liver microsomes. ,,,,, Similarly, the oxidation of PCB metabolites at the para or meta position is commonly observed in mammalian model systems, both in vitro and in vivo . − ,,,, Studies with rats exposed to PCB3 through inhalation identified 3′-, 4′-, and 3-PCB3 sulfate isomers and 3′,4′-di-OH-3 conjugates. , Interestingly, rats receiving an intraperitoneal injection of PCB3 excreted 2′-, 3′-, and 4′-PCB3 sulfate in the urine, suggesting that ortho -hydroxylated PCB3 metabolites are formed in rats in vivo . 2′-OH-3, 3′-OH-3, and 4′-OH-3, together with two unidentified monohydroxylated metabolites, were observed in a metabolism study with rat liver microsomes .…”

“…This observation suggests that HepG2 cells metabolize lower chlorinated PCBs in a congener-specific manner. Congener-specific differences in the metabolism of lower chlorinated PCBs have been documented for studies with purified rat cytochrome P450 enzymes, rat liver microsomes, or liver tissue slices from mice. ,− In-depth metabolism studies with lower chlorinated PCBs have not been reported for human model systems; however, higher chlorinated PCBs are metabolized in a congener-specific manner by human cytochrome P450 enzymes. ,,, …”

“…The use of rat models represents a limitation of studies of the metabolism and toxicity of PCB3 due to species differences in the oxidative metabolism, as has been shown for several higher chlorinated PCBs. , Despite the use of human cell lines for PCB3 toxicity studies, , the metabolism of PCB3 has not been characterized in human models. It is unknown to which degree the PCB3 metabolites formed in humans differ from those formed in rats.…”

Enantioselective Partitioning of Polychlorinated Biphenyls in a HepG2 Cell Culture System: Experimental and Modeling Results

“…Metabolism studies with human liver microsome showed a depletion of (+)-PCB 91, 42 metabolism studies. 34,40,42,60 Consistent with this interpretation, we have demonstrated that the binding of PCB 136 atropisomers to rat cytochrome P450 enzymes 18 does not predict the atropselective metabolism of racemic PCB 136 by rat liver microsomes. 33 The results for the enantioselective analyses demonstrate that in vitro metabolism and toxicity studies with chiral compounds, including PCBs, should take their enantioselective partitioning into account.…”

Twenty years of exceptional success: The molecular education and research consortium in undergraduate computational chemistry (MERCURY)

“…The faculty published 2 peer‐reviewed books, [ 238,239 ] 9 peer‐reviewed book chapters, [ 240–248 ] and 115 peer‐reviewed research papers. [ 249–363 ] This comes to 1.6 peer‐reviewed products/faculty/year during the 3‐year grant period, which is 3.2 times the rate of publication for natural science faculty at PUIs. [ 46 ]…”