Metabolism of 2,3,5,6-tetrachlorobiphenyl-14C and 2,3,4,5,6-pentachlorobiphenyl-14C in the rat

3,3'-Dichlorobiphenyl (PCB 11) is a byproduct of industrial processes and detected in environmental samples. PCB 11 and its metabolites are present in human serum, and emerging evidence demonstrates that PCB 11 is a developmental neurotoxicant. However, little is known about the metabolism of PCB 11 in humans. Here we investigated the metabolism of PCB 11 and the associated metabolomics changes in HepG2 cells using untargeted high-resolution mass spectrometry. HepG2 cells were exposed for 24 h to PCB 11 in DMSO or DMSO alone. Cell culture media were analyzed with ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry. Thirty different metabolites were formed by HepG2 cells exposed to 10 μM PCB 11, including monohydroxylated, dihydroxylated, hydroxylatedmethoxylated, and methoxylated-di-hydroxylated metabolites, and the corresponding sulfo and glucuronide conjugates. The methoxylated PCB metabolites were observed for the first time in a human-relevant model. 4-OH-PCB 11 (3,3'-dichlorobiphenyl-4-ol) and the corresponding catechol metabolite, 4,5-di-OH-PCB 11 (3',5-dichloro-3,4-dihydroxybiphenyl), were unambiguously

Section: Resultsmentioning

confidence: 97%

3,3′-Dichlorobiphenyl Is Metabolized to a Complex Mixture of Oxidative Metabolites, Including Novel Methoxylated Metabolites, by HepG2 Cells

Zhang

Flor

Ruíz

et al. 2020

“…We did not detect the corresponding MeO-OH-PCB3 metabolites (i.e., methylation products of the catechol metabolite , ), probably because these compounds were rapidly biotransformed to sulfate and glucuronide conjugates. MeO-OH-PCB3 metabolites have been observed in the excreta from rats, rabbits, and guinea pigs but have not been detected in humans. Methoxylated and hydroxylated PCB metabolites and their sulfate conjugates were also reported in mice exposed to a PCB mixture .…”

Section: Resultsmentioning

confidence: 99%

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

Zhang

Flor

Ruíz

et al. 2021

The characterization of the metabolism of lower chlorinated PCB, such as 4-chlorobiphenyl (PCB3), is challenging because of the complex metabolite mixtures formed in vitro and in vivo. We performed parallel metabolism studies with PCB3 and its hydroxylated metabolites to characterize the metabolism of PCB3 in HepG2 cells using nontarget high-resolution mass spectrometry (Nt-HRMS). Briefly, HepG2 cells were exposed for 24 h to 10 μM PCB3 or its seven hydroxylated metabolites in DMSO or DMSO alone. Six classes of metabolites were identified with Nt-HRMS in the culture medium exposed to PCB3, including monosubstituted metabolites at the 3′-, 4′-, 3-, and 4-(1,2-shift product) positions and disubstituted metabolites at the 3′,4′-position. 3′,4′-Di-OH-3 (4′-chloro-3,4-dihydroxybiphenyl), which can be oxidized to a reactive and toxic PCB3 quinone, was a central metabolite that was rapidly methylated. The resulting hydroxylated-methoxylated metabolites underwent further sulfation and, to a lesser extent, glucuronidation. Metabolomic analyses revealed an altered tryptophan metabolism in HepG2 cells following PCB3 exposure. Some PCB3 metabolites were associated with alterations of endogenous metabolic pathways, including amino acid metabolism, vitamin A (retinol) metabolism, and bile acid biosynthesis. Indepth studies are needed to investigate the toxicities of PCB3 metabolites, especially the 3′,4′-di-OH-3 derivatives identified in this study.

“…These compounds were found neither in the cultivation media samples nor in the PCB-untreated control extracts. Although previously identified in fungi (40), rats (44), and rabbits (45), as far as we are aware, the presence of PCB methoxy-metabolites in plants has not previously been reported in the literature.…”

Section: Resultsmentioning

confidence: 75%

Hydroxy-PCBs, Methoxy-PCBs and Hydroxy-Methoxy-PCBs: Metabolites of Polychlorinated Biphenyls Formed In Vitro by Tobacco Cells

Rezek

Macek

Macková

et al. 2008

While the metabolism of polychlorinated biphenyls (PCBs) in plant cells is a rarely studied field, hydroxy-PCBs have been detected in several studies involving the use of various plant species. The ability of the tobacco (Nicotiana tabacum) callus culture WSC-38 to metabolize six dichlorobiphenyls under aseptic conditions was studied, and the resulting PCB metabolites were analyzed. WSC-38 cultures were cultivated with individual dichlorinated PCB congeners. The metabolites were identified based on mass spectra characteristics after gas chromatography separation. In addition, metabolites of PCB 9 (2,5-dichlorobiphenyl) were identified by comparing their retention characteristics with the available standards. In most cases at least two hydroxy-PCBs were produced from each parent PCB. Methoxy-PCBs and hydroxy-methoxy-PCBs were other groups of metabolites produced. To the best of our knowledge, ours is the first report to determine the presence of methoxy- and hydroxy-methoxy-metabolites of PCBs in plants. The role of the O-methyltransferases (OMTs) in the methylation of hydroxy-PCBs is discussed. As methoxy-metabolites of acetophenone were found among our samples, we posit that the OMTs responsible for the methylation of these compounds are also involved in the metabolism of PCBs in cultures of WSC-38.