2,2',4,4',5,5'-Hexachlorobiphenyl (T3D0542)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (11)XML
Targets (11)
Record Information
Version2.0
Creation Date2009-03-06 18:59:02 UTC
Update Date2014-12-24 20:22:13 UTC
Accession NumberT3D0542
Identification
Common Name2,2',4,4',5,5'-Hexachlorobiphenyl
ClassSmall Molecule
Description2,2',4,4',5,5'-Hexachlorobiphenyl is one of 209 polychlorinated biphenyls (PCBs). PCBs are a group of synthetic organic compounds with 1-10 chlorine atoms attached to biphenyl. They were manufactured as commercial mixtures but banned in the 1970's because they were found to bioaccumulate and cause harmful health effects. However, PCBs do not break down readily and are still found in the environment. (8)
Compound Type
  • Aromatic Hydrocarbon
  • Coolant
  • Industrial/Workplace Toxin
  • Organic Compound
  • Organochloride
  • Plasticizer
  • Pollutant
  • Polychlorinated Biphenyl
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
2,2',4,4',5,5'-Hexachloro-1,1'-biphenyl
2,2',4,4',5,5'-Hexachloro-1,1'biphenyl
2,2',4,4',5,5'-PCB
2,2',4,4'5,5'-Hexachlorobiphenyl
2,4,5,2',4',5'-Hexachloro-1,1'-biphenyl
2,4,5,2',4',5'-Hexachlorobiphenyl
Hexachlorobiphenyl
PCB 153
Chemical FormulaC12H4Cl6
Average Molecular Mass360.878 g/mol
Monoisotopic Mass357.844 g/mol
CAS Registry Number35065-27-1
IUPAC Name1,2,4-trichloro-5-(2,4,5-trichlorophenyl)benzene
Traditional Namehexachlorobiphenyl
SMILESClC1=CC(Cl)=C(C=C1Cl)C1=CC(Cl)=C(Cl)C=C1Cl
InChI IdentifierInChI=1S/C12H4Cl6/c13-7-3-11(17)9(15)1-5(7)6-2-10(16)12(18)4-8(6)14/h1-4H
InChI KeyInChIKey=MVWHGTYKUMDIHL-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as polychlorinated biphenyls. These are organic compounds containing at least two chlorine atoms attached to either benzene ring of the biphenyl moiety.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassBiphenyls and derivatives
Direct ParentPolychlorinated biphenyls
Alternative Parents
Substituents
  • Polychlorinated biphenyl
  • Halobenzene
  • Chlorobenzene
  • Aryl halide
  • Aryl chloride
  • Hydrocarbon derivative
  • Organochloride
  • Organohalogen compound
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceOily liquids or solids that are colorless to light yellow.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility9.5e-07 mg/mL at 24°C [CHIOU,CT et al. (1977)]
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility2.2e-06 g/LALOGPS
logP7.25ALOGPS
logP7.24ChemAxon
logS-8.2ALOGPS
Physiological Charge0ChemAxon
Hydrogen Acceptor Count0ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area0 ŲChemAxon
Rotatable Bond Count1ChemAxon
Refractivity80.02 m³·mol⁻¹ChemAxon
Polarizability31.19 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0bt9-0129000000-0d67f8cb13767ea513192021-09-23View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-0009000000-909704e283ebc238d5092016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a4i-0009000000-b1d1f6af5ad2cd4389852016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4i-0019000000-c2d5eb820e43cadc43a02016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0009000000-71bc1bc7e8d4749ca24d2016-08-04View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-0009000000-71bc1bc7e8d4749ca24d2016-08-04View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4i-0029000000-aa8cab8137f553f10c5c2016-08-04View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-0009000000-df7a45438bba66dda2212021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a4i-0009000000-df7a45438bba66dda2212021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4i-0098000000-da35aa22f16c88cfee6a2021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0009000000-78bafa0445818d9cc4ba2021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-0009000000-78bafa0445818d9cc4ba2021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0zfr-0095000000-b429fe597808889d934d2021-10-12View Spectrum
MSMass Spectrum (Electron Ionization)splash10-08fv-4944000000-db2ecb8089788a24b9a02014-09-20View Spectrum
1D NMR1H NMR Spectrum (1D, 300 MHz, CDCl3, experimental)Not Available2014-09-20View Spectrum
1D NMR13C NMR Spectrum (1D, 100.41 MHz, CDCl3, experimental)Not Available2014-09-23View Spectrum
Toxicity Profile
Route of ExposureOral (8) ; inhalation (8) ; dermal (8)
Mechanism of ToxicityThe mechanism of action varies with the specific PCB. Dioxin-like PCBs bind to the aryl hydrocarbon receptor, which disrupts cell function by altering the transcription of genes, mainly be inducing the expression of hepatic Phase I and Phase II enzymes, especially of the cytochrome P450 family. Most of the toxic effects of PCBs are believed to be results of Ah receptor binding. Other PBCs are believed to interfere with calcium channels and/or change brain dopamine levels. PCBs can also cause endocrine disurption by altering the production of thyroid hormones and binding to estrogen receptors, which can stimulate the growth of certain cancer cells and produce other estrogenic effects, such as reproductive dysfunction. They will bioaccumulate by binding to receptor proteins such as uteroglobin. (1, 2, 4, 5)
MetabolismPCBs are absorbed via inhalation, oral, and dermal routes of exposure. They are trasported in the blood, often bound to albumin. Due to their lipophilic nature they tend to accumulate in lipid-rich tissues, such as the liver, adipose, and skin. Metabolism of PCBs is very slow and varies based on the degree and position of chlorination. PCBs are metabolized by the microsomal monooxygenase system catalyzed by cytochrome P-450 enzymes to polar metabolites that can undergo conjugation with glutathione and glucuronic acid. The major metabolites are hydroxylated products which are excreted in the bile and faeces. The slow metabolism of PCBs means they tend to accumulate in body tissues. (8, 6)
Toxicity ValuesLD50: 1010 mg/kg (Oral, Rat) (7) LD50: 880 mg/kg (Intraperitoneal, Mouse) (7)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)1, carcinogenic to humans. (10)
Uses/SourcesPCBs were used as coolants and lubricants in transformers, capacitors, and other electrical devices (such as fluorescent lights and refridgerators) produced before 1977. PCBs may contaminate the air and water near hazardous waste sites. In addition, PCBs bioaccumulate in the environment and may be found in fish, meat, and dairy products. (8)
Minimum Risk LevelIntermediate Oral: 0.03 ug/kg/day (9)
Health EffectsThe most common health effects of PCBs are skin conditions such as chloracne and rashes. Chronic PCB exposure has also been shown to cause liver, stomach and kidney, damage, jaundice, edema, anemia, changes in the immune system, behavioral alterations, and impaired reproduction. (8)
SymptomsChronic PCB exposure results in symptoms such as abdominal pain, nausea, vomiting, diarrhea, headache, dizziness, depression, nervousness, dermal and ocular lesions, fatigue, irregular menstrual cycles and a lowered immune response. (1)
TreatmentThere are no specific treatments for PCB poisoning, since it is not usually recognized until after substantial chronic exposure. Only preventing further exposure and treating the observed symptoms can be done. Acute inhalation can be treated by administering oxygen. (8)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDNot Available
PubChem Compound ID37034
ChEMBL IDCHEMBL14377
ChemSpider ID33983
KEGG IDC14201
UniProt IDNot Available
OMIM ID
ChEBI ID34202
BioCyc IDCPD-946
CTD IDC014024
Stitch ID2,2',4,4',5,5'-Hexachlorobiphenyl
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkNot Available
References
Synthesis ReferenceNot Available
MSDSNot Available
General References
  1. Aoki Y: Polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans as endocrine disrupters--what we have learned from Yusho disease. Environ Res. 2001 May;86(1):2-11. [11386736 ]
  2. Safe S, Bandiera S, Sawyer T, Robertson L, Safe L, Parkinson A, Thomas PE, Ryan DE, Reik LM, Levin W, et al.: PCBs: structure-function relationships and mechanism of action. Environ Health Perspect. 1985 May;60:47-56. [2992927 ]
  3. Horowitz Y, Greenberg D, Ling G, Lifshitz M: Acrodynia: a case report of two siblings. Arch Dis Child. 2002 Jun;86(6):453. [12023189 ]
  4. Troisi GM, Haraguchi K, Kaydoo DS, Nyman M, Aguilar A, Borrell A, Siebert U, Mason CF: Bioaccumulation of polychlorinated biphenyls (PCBs) and dichlorodiphenylethane (DDE) methyl sulfones in tissues of seal and dolphin morbillivirus epizootic victims. J Toxicol Environ Health A. 2001 Jan 12;62(1):1-8. [11205532 ]
  5. Kester MH, Bulduk S, Tibboel D, Meinl W, Glatt H, Falany CN, Coughtrie MW, Bergman A, Safe SH, Kuiper GG, Schuur AG, Brouwer A, Visser TJ: Potent inhibition of estrogen sulfotransferase by hydroxylated PCB metabolites: a novel pathway explaining the estrogenic activity of PCBs. Endocrinology. 2000 May;141(5):1897-900. [10803601 ]
  6. World Health Organization (1993). Environ Health Criteria 140: Polychlorniated Biphenyls and Terphenyls.
  7. Lewis RJ (1996). Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold.
  8. ATSDR - Agency for Toxic Substances and Disease Registry (2000). Toxicological profile for polychlorinated biphenyls. U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA). [Link]
  9. ATSDR - Agency for Toxic Substances and Disease Registry (2001). Minimal Risk Levels (MRLs) for Hazardous Substances. U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA). [Link]
  10. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

Target Details
1. Estrogen receptor
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
References
  1. Taccone-Gallucci M, Manca-di-Villahermosa S, Battistini L, Stuffler RG, Tedesco M, Maccarrone M: N-3 PUFAs reduce oxidative stress in ESRD patients on maintenance HD by inhibiting 5-lipoxygenase activity. Kidney Int. 2006 Apr;69(8):1450-4. [16531984 ]
  2. Tavolari S, Bucci L, Tomasi V, Guarnieri T: Selected polychlorobiphenyls congeners bind to estrogen receptor alpha in human umbilical vascular endothelial (HUVE) cells modulating angiogenesis. Toxicology. 2006 Jan 20;218(1):67-74. Epub 2005 Nov 15. [16293362 ]
  3. Luft S, Milki E, Glustrom E, Ampiah-Bonney R, O'Hara P. Binding of Organochloride and Pyrethroid Pesticides To Estrogen Receptors α and β: A Fluorescence Polarization Assay. Biophysical Journal 2009;96(3):444a.
Target Details
2. Estrogen receptor beta
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual.
Gene Name:
ESR2
Uniprot ID:
Q92731
Molecular Weight:
59215.765 Da
References
  1. Taccone-Gallucci M, Manca-di-Villahermosa S, Battistini L, Stuffler RG, Tedesco M, Maccarrone M: N-3 PUFAs reduce oxidative stress in ESRD patients on maintenance HD by inhibiting 5-lipoxygenase activity. Kidney Int. 2006 Apr;69(8):1450-4. [16531984 ]
  2. Luft S, Milki E, Glustrom E, Ampiah-Bonney R, O'Hara P. Binding of Organochloride and Pyrethroid Pesticides To Estrogen Receptors α and β: A Fluorescence Polarization Assay. Biophysical Journal 2009;96(3):444a.
Target Details
3. Estrogen sulfotransferase
General Function:
Sulfotransferase activity
Specific Function:
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of estradiol and estrone. May play a role in the regulation of estrogen receptor activity by metabolizing free estradiol. Maximally sulfates beta-estradiol and estrone at concentrations of 20 nM. Also sulfates dehydroepiandrosterone, pregnenolone, ethinylestradiol, equalenin, diethylstilbesterol and 1-naphthol, at significantly higher concentrations; however, cortisol, testosterone and dopamine are not sulfated.
Gene Name:
SULT1E1
Uniprot ID:
P49888
Molecular Weight:
35126.185 Da
References
  1. Aoki Y: Polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans as endocrine disrupters--what we have learned from Yusho disease. Environ Res. 2001 May;86(1):2-11. [11386736 ]
  2. Kester MH, Bulduk S, Tibboel D, Meinl W, Glatt H, Falany CN, Coughtrie MW, Bergman A, Safe SH, Kuiper GG, Schuur AG, Brouwer A, Visser TJ: Potent inhibition of estrogen sulfotransferase by hydroxylated PCB metabolites: a novel pathway explaining the estrogenic activity of PCBs. Endocrinology. 2000 May;141(5):1897-900. [10803601 ]
Target Details
4. Aromatic-L-amino-acid decarboxylase
General Function:
Pyridoxal phosphate binding
Specific Function:
Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine.
Gene Name:
DDC
Uniprot ID:
P20711
Molecular Weight:
53925.815 Da
References
  1. ATSDR - Agency for Toxic Substances and Disease Registry (2000). Toxicological profile for polychlorinated biphenyls. U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA). [Link]
Target Details
5. Aryl hydrocarbon receptor
General Function:
Transcription regulatory region dna binding
Specific Function:
Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1.
Gene Name:
AHR
Uniprot ID:
P35869
Molecular Weight:
96146.705 Da
References
  1. Safe S, Bandiera S, Sawyer T, Robertson L, Safe L, Parkinson A, Thomas PE, Ryan DE, Reik LM, Levin W, et al.: PCBs: structure-function relationships and mechanism of action. Environ Health Perspect. 1985 May;60:47-56. [2992927 ]
Target Details
6. Mitogen-activated protein kinase 1
General Function:
Rna polymerase ii carboxy-terminal domain kinase activity
Specific Function:
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Mediates phosphorylation of TPR in respons to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation.Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity.
Gene Name:
MAPK1
Uniprot ID:
P28482
Molecular Weight:
41389.265 Da
References
  1. Tavolari S, Bucci L, Tomasi V, Guarnieri T: Selected polychlorobiphenyls congeners bind to estrogen receptor alpha in human umbilical vascular endothelial (HUVE) cells modulating angiogenesis. Toxicology. 2006 Jan 20;218(1):67-74. Epub 2005 Nov 15. [16293362 ]
Target Details
7. Mitogen-activated protein kinase 3
General Function:
Phosphatase binding
Specific Function:
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade.
Gene Name:
MAPK3
Uniprot ID:
P27361
Molecular Weight:
43135.16 Da
References
  1. Tavolari S, Bucci L, Tomasi V, Guarnieri T: Selected polychlorobiphenyls congeners bind to estrogen receptor alpha in human umbilical vascular endothelial (HUVE) cells modulating angiogenesis. Toxicology. 2006 Jan 20;218(1):67-74. Epub 2005 Nov 15. [16293362 ]
Target Details
8. Nuclear receptor subfamily 1 group I member 2
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
Gene Name:
NR1I2
Uniprot ID:
O75469
Molecular Weight:
49761.245 Da
References
  1. Kretschmer XC, Baldwin WS: CAR and PXR: xenosensors of endocrine disrupters? Chem Biol Interact. 2005 Aug 15;155(3):111-28. [16054614 ]
Target Details
9. Transthyretin
General Function:
Identical protein binding
Specific Function:
Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.
Gene Name:
TTR
Uniprot ID:
P02766
Molecular Weight:
15886.88 Da
References
  1. Hamers T, Kamstra JH, Cenijn PH, Pencikova K, Palkova L, Simeckova P, Vondracek J, Andersson PL, Stenberg M, Machala M: In vitro toxicity profiling of ultrapure non-dioxin-like polychlorinated biphenyl congeners and their relative toxic contribution to PCB mixtures in humans. Toxicol Sci. 2011 May;121(1):88-100. doi: 10.1093/toxsci/kfr043. Epub 2011 Feb 25. [21357386 ]
Target Details
10. Tyrosine 3-monooxygenase
General Function:
Tyrosine 3-monooxygenase activity
Specific Function:
Plays an important role in the physiology of adrenergic neurons.
Gene Name:
TH
Uniprot ID:
P07101
Molecular Weight:
58599.545 Da
References
  1. ATSDR - Agency for Toxic Substances and Disease Registry (2000). Toxicological profile for polychlorinated biphenyls. U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA). [Link]
Target Details
11. Uteroglobin
General Function:
Polychlorinated biphenyl binding
Specific Function:
Binds phosphatidylcholine, phosphatidylinositol, polychlorinated biphenyls (PCB) and weakly progesterone, potent inhibitor of phospholipase A2.
Gene Name:
SCGB1A1
Uniprot ID:
P11684
Molecular Weight:
9993.6 Da
References
  1. Troisi GM, Haraguchi K, Kaydoo DS, Nyman M, Aguilar A, Borrell A, Siebert U, Mason CF: Bioaccumulation of polychlorinated biphenyls (PCBs) and dichlorodiphenylethane (DDE) methyl sulfones in tissues of seal and dolphin morbillivirus epizootic victims. J Toxicol Environ Health A. 2001 Jan 12;62(1):1-8. [11205532 ]