Polychlorinated biphenyl quinone induces mitochondrial‐mediated and caspase‐dependent apoptosis in HepG2 cells

Xu, Dan; Li, Lingrui; Liu, Lichao; Dong, Hui; Deng, Qin; Yang, Xi; Song, Erqun; Song, Yang

doi:10.1002/tox.21979

Cited by 23 publications

(37 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Upon absorption, PCB is metabolically activated by cytochrome P-450 and oxidized into arene oxide or radical intermediates, which can form covalent adducts with cellular components, like DNA and proteins (44). Hydroxylated PCB metabolites have been identified as the most abundant metabolites (18), and their oxidized forms, PCB quinones, have been suggested to induce oxidative DNA damage, genotoxicity, and mitochondria-mediated cell apoptosis in our previous studies (15,39,70). In the current study, we assessed the effect of PCB29-pQ on HUVEC permeability and junction disassembly.…”

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

Polychlorinated biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling

Zhang

Feng

Bai

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling. Am J Physiol Heart Circ Physiol 308: H1205-H1214, 2015. First published March 13, 2015; doi:10.1152/ajpheart.00005.2015.-Environmental hazardous material polychlorinated biphenyl (PCB) exposure is associated with vascular endothelial dysfunction, which may increase the risk of cardiovascular diseases and cancer metastasis. Our previous studies illustrated the cytotoxic, antiproliferative, and genotoxic effects of a synthetic, quinone-type, highly reactive metabolite of PCB, 2,3,5-trichloro-6-phenyl-[1,4]benzoquinone (PCB29-pQ). Here, we used it as the model compound to investigate its effects on vascular endothelial integrity and permeability. We demonstrated that noncytotoxic doses of PCB29-pQ induced vascular endothelial (VE)-cadherin junction disassembly by increasing the phosphorylation of VE-cadherin at Y658. We also found that focal adhesion assembly was required for PCB29-pQ-induced junction breakdown. Focal adhesion site-associated actin stress fibers may serve as holding points for cytoskeletal tension to regulate the cellular contractility. PCB29-pQ exposure promoted the association of actin stress fibers with paxillincontaining focal adhesion sites and enlarged the size/number of focal adhesions. In addition, PCB29-pQ treatment induced phosphorylation of paxillin at Y118. By using pharmacological inhibition, we further demonstrated that p38 activation was necessary for paxillin phosphorylation, whereas extracellular signal-regulated kinases-1/2 activation regulated VE-cadherin phosphorylation. In conclusion, these results indicated that PCB29-pQ stimulates endothelial hyperpermeability by mediating VE-cadherin disassembly, junction breakdown, and focal adhesion formation. Intervention strategies targeting focal adhesion and MAPK signaling could be used as therapeutic approaches for preventing adverse cardiovascular health effects induced by environmental toxicants such as PCBs.

show abstract

Section: Discussionmentioning

confidence: 91%

“…PCB29-pQ was previously reported to mediate apoptosis of human hepatocellular liver carcinoma (HepG2) cells (70). To examine the cytotoxicity of PCB29-pQ on HUVECs, we measured the dose and time effect of PCB29-pQ on HUVEC viability by MTT assay.…”

Section: Pcb29mentioning

confidence: 99%

Polychlorinated biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling

Zhang

Feng

Bai

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, the release of cytochrome c into the cytoplasm activates caspase-dependent apoptosis (Spierings et al 2005). PCB3 quinone was reported to increase oxidative stress in the mitochondria of human cells in culture and to inhibit the mitochondrial electron chain; PCB29 quinone caused an increase in mitochondrial oxidative stress, a transfer of cytochrome c from the mitochondria into the cytoplasm, and induced caspase-dependent apoptosis (Xiao et al 2014, Xiao et al 2013, Xu et al 2014, Xu et al 2015, Zhu et al 2009). These reports suggest that cytochrome c may play a crucial role in PCB quinone toxicity.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome c adducts with PCB quinoid metabolites

Teesch

Murry

et al. 2015

Environ Sci Pollut Res

View full text Add to dashboard Cite

PCBs are a group of 209 individual congeners widely used as industrial chemicals. PCBs are found as by-products in dye and paint manufacture and are legacy, ubiquitous and persistent as human and environmental contaminants. PCBs with fewer chlorine atoms may be metabolized to hydroxy- and dihydroxy- metabolites and further oxidized to quinoid metabolites both in vitro and in vivo. Specifically, quinoid metabolites may form adducts on nucleophilic sites within cells. We hypothesized that the PCB-quinones covalently bind to cytochrome c and thereby cause defects in the function of cytochrome c. In this study synthetic PCB quinones (2-(4’-chlorophenyl)-1,4-benzoquinone, 2-(3’, 5’-dichlorophenyl)-1,4-benzoquinone, 2-(3’,4’, 5’-trichlorophenyl)-1,4-benzoquinone, and 2-(4’-chlorophenyl)-3,6-dichloro-1,4-benzoquinone) were incubated with cytochrome c, and adducts were detected by LC-MS and MALDI TOF. SDS PAGE gel electrophoresis was employed to separate the adducted proteins, while trypsin digestion and LC-MS/MS were applied to identify the amino acid binding sites on cytochrome c. Conformation change of cytochrome c after binding with PCB3-para-quinone was investigated by SYBYL-X simulation and cytochrome c function was examined. We found that more than one molecule of PCB-quinone may bind to one molecule of cytochrome c. Lysine and glutamic acid were identified as the predominant binding sites. Software simulation showed conformation changes of adducted cytochrome c. Additionally, cross-linking of cytochrome c was observed on the SDS PAGE gel. Cytochrome c was found to be in the reduced form after incubation with PCB quinones. These data provide evidence that the covalent binding of PCB quinone metabolites to cytochrome c may be included among the toxic effects of PCBs.

show abstract

“…24, 25 In fact, the analysis of oxidized metabolites such as hydroxylated PCBs (OH-PCBs) has been completed in biological samples from various species worldwide. 5, 26, 27 Further oxidation of OH-PCBs to catechols, p -hydroquinones, and quinones has been linked to cytotoxic formation of reactive oxygen species 28, 29 and the potential for carcinogenicity. 30 Other PCB metabolites include PCB sulfates and glucuronides, as well as glutathione conjugates and their mercapturic acid derivatives.…”

Section: Introductionmentioning

confidence: 99%

Sulfation of Lower Chlorinated Polychlorinated Biphenyls Increases Their Affinity for the Major Drug-Binding Sites of Human Serum Albumin

Rodríguez

Lehmler

et al. 2016

Environ. Sci. Technol.

View full text Add to dashboard Cite

The disposition of toxicants is often affected by their binding to serum proteins, of which the most abundant in humans is serum albumin (HSA). There is increasing interest in the toxicities of environmentally persistent polychlorinated biphenyls (PCBs) with lower numbers of chlorine atoms (LC-PCBs) due to their presence in both indoor and outdoor air. PCB sulfates derived from metabolic hydroxylation and sulfation of LC-PCBs have been implicated in endocrine disruption due to high affinity-binding to the thyroxine-carrying protein, transthyretin. Interactions of these sulfated metabolites of LC-PCBs with HSA, however, have not been previously explored. We have now determined the relative HSA-binding affinities for a group of LC-PCBs and their hydroxylated and sulfated derivatives by selective displacement of the fluorescent probes 5-dimethylamino-1-naphthalenesulfonamide and dansyl--proline from the two major drug-binding sites on HSA (previously designated as Site I and Site II). Values for half-maximal displacement of the probes indicated that the relative binding affinities were generally PCB sulfate ≥ OH-PCB > PCB, although this affinity was site- and congener-selective. Moreover, specificity for Site II increased as the numbers of chlorine atoms increased. Thus, hydroxylation and sulfation of LC-PCBs result in selective interactions with HSA which may affect their overall retention and toxicity.

show abstract

Polychlorinated biphenyl quinone induces mitochondrial‐mediated and caspase‐dependent apoptosis in HepG2 cells

Cited by 23 publications

References 47 publications

Polychlorinated biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling

Polychlorinated biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling

Cytochrome c adducts with PCB quinoid metabolites

Sulfation of Lower Chlorinated Polychlorinated Biphenyls Increases Their Affinity for the Major Drug-Binding Sites of Human Serum Albumin

Contact Info

Product

Resources

About