Determination of the human cytochrome P450 monooxygenase catalyzing the enantioselective oxidation of 2,2′,3,5′,6-pentachlorobiphenyl (PCB 95) and 2,2′,3,4,4′,5′,6-heptachlorobiphenyl (PCB 183)

Nagayoshi, Haruna; Kakimoto, Kensaku; Konishi, Yoshimasa; Kajimura, K.; Nakano, Takeshi

doi:10.1007/s11356-017-0434-z

Cited by 10 publications

(18 citation statements)

References 26 publications

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“…For example, ADMET Predictor did not predict PCB metabolism via arene oxide intermediates (discussed below), and MetaDrug did not predict that oxidation of PCBs by CYP2E1. Moreover, the formation of the 1,2-shift products was not predicted by either software package, whereas both ADMET Predictor and Metadrug predicted PCB metabolism by CYP1A2, a P450 isoform that does not metabolize PCB congeners with multiple ortho substituents based on published metabolism studies. ,,, …”

Section: Resultsmentioning

confidence: 98%

“…In contrast, enrichment of E 1 -4-91 was observed in studies with HLMs (EF = 0.75). Because 4′-95 is the major metabolite formed by CYP2A6, the enrichment of E 2 -4′-95 likely explains the enrichment of aR-PCB 95 [(−)-PCB 95] reported by an earlier metabolism study with CYP2A6; however, metabolism studies with pure PCB 95 atropisomers are needed to confirm this hypothesis.…”

Section: Resultsmentioning

confidence: 99%

“…Rat CYP1A1 oxidizes non-ortho-chlorinated PCBs preferentially in the para position of the biphenyl moiety, whereas rat CYP2B1 preferentially oxidizes ortho-substituted PCB congeners in the meta position . PCB 136 is also metabolized by CYP2B enzymes in dogs, rats, and mice, but not rabbits to a meta-hydroxylated metabolite. − A handful of studies have identified human P450 isoforms involved in the metabolism of PCBs, including CYP2A6 − and CYP2B6. ,, CYP2A6 selectively oxidizes ortho-substituted PCB congeners, such as PCB 52 (2,2′,5,5′-tetrachlorobiphenyl) and PCB 101 (2,2′,4,5,5′-pentachlorobiphenyl), in the para position. , CYP2B6 is another human P450 isoform that metabolizes ortho-substituted PCBs, , but with regioselectivity that is distinctively different from CYP2A6. PCB 153 (2,2′,4,4′,5,5′-hexachlorobiphenyl) is metabolized by CYP2B6 to 2,2′,4,4′,5,5′-hexachlorobiphenyl-3-ol, a meta hydroxylated metabolite .…”

Section: Introductionmentioning

confidence: 99%

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

Uwimana

Ruíz

et al. 2018

Environ. Sci. Technol.

106

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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.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Uwimana

Ruíz

et al. 2018

Environ. Sci. Technol.

106

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“…The atropisomer eluting first on a CD column (E 1 ) was significantly enriched in both cells and dishes for PCB 91 (i.e., (−)-PCB 91; EF values of 0.77 for cells and 0.68 for dishes), PCB 132 (i.e., (−)-PCB 132; EF values of 0.69 for cells and 0.63 for dishes), and PCB 136 (i.e., (−)-PCB 136; EF values of 0.55 for cells and 0.68 for dishes). A slight enrichment of E 1 -PCB 95 (i.e., aR- or (−)-PCB 95) was observed, with EF values of 0.55 for cells and 0.53 for dishes. It is noteworthy that the direction of the atropisomeric enrichment in cells and dishes was identical for all four PCB congeners investigated.…”

Section: Resultsmentioning

confidence: 97%

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

Zhang

Flor

Ludewig

et al. 2020

Environ. Sci. Technol.

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Cell culture models are used to study the toxicity of polychlorinated biphenyls (PCBs); however, it is typically unknown how much PCB enters the cells and, for chiral PCBs, if the partitioning is atropselective. We investigated the partitioning of racemic PCB 91, PCB 95, PCB 132, and PCB 136 in HepG2 cells following a 72 h incubation. PCBs were present in the cell culture medium (60.7–88.8%), cells (8.0–14.6%), and dishes (2.3–7.8%) and displayed atropisomeric enrichment in the cells (enantiomeric fraction [EF] = 0.55–0.77) and dishes (EF = 0.53–0.68). Polyparameter linear free energy relationships coupled with a composition-based model provided a good estimate of the PCB levels in the cells and cell culture medium. The free concentration was subsequently used to extrapolate from the nominal cell culture concentration to PCB tissue levels and vice versa. This approach can be used for in vitro–in vivo extrapolations for all 209 PCB congeners. However, this model (and modified models based on descriptors incorporating atropselective interactions, i.e., relative retention times on chiral columns) did not predict the atropselective partitioning in the cell culture system. Improved chemical descriptors that account for the atropselective binding of PCBs to biological macromolecules are, therefore, needed to predict the atropselective partitioning of PCBs in biological systems.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Uwimana

Cagle

Yeung

et al. 2018

Preprint

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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 demonstrated 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 132atropisomers. These findings suggest that there are inter-individual 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.

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Determination of the human cytochrome P450 monooxygenase catalyzing the enantioselective oxidation of 2,2′,3,5′,6-pentachlorobiphenyl (PCB 95) and 2,2′,3,4,4′,5′,6-heptachlorobiphenyl (PCB 183)

Cited by 10 publications

References 26 publications

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

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

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

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

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