2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Is Atropselectively Metabolized to para-Hydroxylated Metabolites by Human Liver Microsomes

Abstract

Exposure to neurotoxic, chiral PCBs has been associated with neurodevelopmental disorders, but their metabolism in humans remains unexplored. We investigated the enantioselective metabolism of PCB 95 by human liver microsomes (HLMs) to potentially neurotoxic, hydroxylated metabolites (OH-PCBs). OH-PCB profiles formed in experiments with HLMs differed from metabolite profiles reported for rodent species. The second eluting atropisomer of 2,2′,3,5′,6-pentachlorobiphenyl-4′-ol, the major metabolite, was preferentially formed by all HLM preparations investigated. Differences in metabolite formation rates were observed with single donor HLMs. The metabolism of PCBs and its role in PCB-mediated neurodevelopmental disorders need to be further characterized.

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

“…Extraction of PCB 132 and its hydroxylated metabolites. PCB 132 and its hydroxylated metabolites were extracted from the incubation mixtures as reported previously Uwimana et al, 2016;Wu et al, 2011). Briefly, PCB 117 (200 ng) and 4'-159 (68.5 ng) were added to each sample as surrogate recovery standards, followed by hydrochloric acid (6 M, 1 mL) and 2-propanol (5 mL).…”

“…To obtain metabolite levels sufficient for GC-TOF/MS analysis, incubations were performed using the following experimental conditions: 50 µM racemic PCB 132, 0.3 mg/mL microsomal protein and 1 mM NADPH for 90 min at 37 °C. Metabolites were extracted and derivatized as described above before analysis on a Waters GCT Premier gas chromatograph (Waters Corporation, Milford, MA, USA) combined with a time-of-flight mass spectrometer in the High-Resolution Mass Spectrometry Facility of the University of Iowa (Iowa City, IA, USA) (Uwimana et al, 2016(Uwimana et al, , 2018. Measurements were performed with and without heptacosafluorotributylamine as lock mass to determine the accurate mass of [M] + and obtain mass spectra of the metabolites.…”

“…were quantified as methylated derivatives on an Agilent 7890A gas chromatograph with a 63 Ni-micro electron capture detector (µECD) and a SPB-1 capillary column (60 m length, 250 µm inner diameter, 0.25 µm film thickness; Supelco, St Louis, MO, USA) as reported earlier (Uwimana et al, 2016;Uwimana et al, 2017;Wu et al, 2013b). PCB 204 was added as internal standard (volume corrector) prior to analysis, and concentrations of OH-PCB 132 metabolites (as methylated derivatives) were determined using the internal standard method Wu et al, 2016;Wu et al, 2011).…”

“…PCB 204 was added as internal standard (volume corrector) prior to analysis, and concentrations of OH-PCB 132 metabolites (as methylated derivatives) were determined using the internal standard method Wu et al, 2016;Wu et al, 2011). Levels of PCB and its metabolites were not adjusted for recovery to facilitate a comparison with earlier studies (Uwimana et al, 2016(Uwimana et al, , 2018Uwimana et al, 2019;Wu et al, 2016). The average RRTs of the metabolites, calculated relative to PCB 204, were within 0.5% of the RRT for the respective standard (European Commission, 2002).…”

“…Biotransformation studies reveal species differences in the atropselective metabolism of PCBs to chiral hydroxylated metabolites (Kania-Korwel et al, 2016a); however, only a few PCB metabolism studies in humans have been reported (Schnellmann et al, 1983;Uwimana et al, 2016Uwimana et al, , 2018Wu et al, 2014). Because PCB 132 is present in the environment, displays atropisomeric enrichment in human samples, and represent a largely unexplored environmental and human health concern, the objective of 5 this study was to investigate the atropselective metabolism of PCB 132 to OH-PCB metabolites by HLMs and assess if PCB 132 atropselectively affects neurotoxic outcomes in dopaminergic cells in culture.…”