Human CYP2A6, CYP2B6, AND CYP2E1 Atropselectively Metabolize Polychlorinated Biphenyls to Hydroxylated Metabolites

Abstract

Exposure to chiral polychlorinated biphenyls (PCBs) has been associated with neurodevelopmental disorders. Their hydroxylated metabolites (OH-PCBs) are also potentially toxic to the developing human brain; however, the formation of OH-PCBs by human cytochrome P450 (P450) isoforms is poorly investigated. To address this knowledge gap, we investigated the atropselective biotransformation of 2,2',3,4',6-pentachlorobiphenyl (PCB 91), 2,2',3,5',6pentachlorobiphenyl (PCB 95), 2,2',3,3',4,6'-hexachlorobiphenyl (PCB 132), and 2,2',3,3',6,6'hexachlorobiphenyl (PCB 136) by different human P450 isoforms. In silico predictions with ADMET Predictor and MetaDrug software suggested a role of CYP1A2, CYP2A6, CYP2B6, CYP2E1, and CYP3A4 in the metabolism of chiral PCBs. Metabolism studies with recombinant human enzymes demonstrated that CYP2A6 and CYP2B6 oxidized PCB 91 and PCB 132 in the meta position and that CYP2A6 oxidized PCB 95 and PCB 136 in the para position. CYP2B6 played only a minor role in the metabolism of PCB 95 and PCB 136 and formed metahydroxylated metabolites. Traces of para-hydroxylated PCB metabolites were detected in incubations with CYP2E1. No hydroxylated metabolites were present in incubations with CYP1A2 or CYP3A4. Atropselective analysis revealed P450 isoform-dependent and congenerspecific atropselective enrichment of OH-PCB metabolites. These findings suggest that CYP2A6 and CYP2B6 play an important role in the oxidation of neurotoxic PCBs to chiral OH-PCBs in humans.

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

“…This observation is not surprising considering the well-documented variability of P450 enzyme activities among humans (Guengerich, 2015). As we reported recently, both CYP2A6 and CYP2B6 are involved in the metabolism of PCB 132 (Uwimana et al, 2019). CYP2A6 primarily formed 3'-140, with 5'-132 and 4'-132 being minor metabolites.…”

“…Moreover, our computational results suggest that the formation of parasubstituted metabolites of PCB 95 and PCB 136 is not merely due to the energetically favored opening of the 3,4-or 4,5-arene oxide intermediates. Instead, congener-specific differences in the steric or electronic interaction of both PCB congeners with P450 isoforms involved in their metabolism (Uwimana et al, 2019) likely affect the ring opening of the putative arene oxide intermediates to OH-PCBs. In contrast, the formation of OH-PCB metabolites of PCB 132 and related PCB congeners in rodents may or may not involve an arene oxide intermediate.…”

“…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).…”

“…The oxidation of PCBs by P450 enzymes occurs by direct insertion of an oxygen atom into an aromatic C-H bond or via an arene oxide intermediate (Forgue et al, 1982;Forgue et al, 1979;Preston et al, 1983). Several P450 isoforms, including CYP2A and CYP2B enzymes, are involved in the metabolism of ortho chlorinated PCB congeners, such as PCB 132, in different species (Lu et al, 2013;McGraw et al, 2006;Nagayoshi et al, 2018;Ohta et al, 2012;Uwimana et al, 2019;Waller et al, 1999;Warner et al, 2009). Hydroxylated and methyl sulfone metabolites of PCB 132 have been detected in human blood, breast milk and feces (Haraguchi et al, 2004;Haraguchi et al, 2005).…”

Polychlorinated Biphenyls (PCBs): Risk Factors for Autism Spectrum Disorder?

“…A key unanswered question in the field is the role of xenobiotic metabolism in determining neurotoxic outcomes following developmental PCB exposures. The cytochrome p450 enzymes play a major role in PCB metabolism, converting the parent compounds to hydroxylated PCBs, which in turn can be further metabolized to glucuronide, sulfate and other conjugates [34,87,88]. PCB metabolites are detected in serum from occupationally exposed humans [89] and pregnant women [90].…”