T3D0077 - Chromium
| Record Information | |
|---|---|
| Version | 1.0 |
| Creation Date | 2009-03-06 18:58:02 UTC |
| Update Date | 2013-04-25 08:32:44 UTC |
| Accession Number | T3D0077 |
| Identification | |
| Common Name | Chromium |
| Description | Chromium is a chemical element which has the symbol Cr and atomic number 24. It naturally occurs in rocks, animals, plants, and soil, and is usually mined as chromite ore. Chromium is a hard metal and is used mainly for making steel. Chromium is most toxic in its +6 oxidation state (chromium(VI)) due to its greater ability to enter cells and higher redox potential. Trivalent chromium (chromium(III)) however, is biologically necessary for sugar and lipid metabolism in humans. (R045) |
| Compound Type |
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| Chemical Structure |
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| Synonyms |
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| Chemical Formula | Cr |
| Average Molecular Weight | 51.9961 |
| Monoisotopic Molecular Weight | 51.940511904 |
| Chemical IUPAC Name | chromium(3+) |
| CAS Registry Number | 7440-47-3 |
| SMILES | [Cr+3] |
| InChI Identifier | InChI=1S/Cr/q+3 |
| InChI Key | InChIKey=BFGKITSFLPAWGI-UHFFFAOYSA-N |
| Chemical Taxonomy | |
| Kingdom | Inorganic Compounds |
| Super Class | Homogeneous Metal Compounds |
| Class | Homogeneous Transition Metal Compounds |
| Sub Class | Not Available |
| Direct Parent | Homogeneous Transition Metal Compounds |
| Alternative Parents | Not Available |
| Molecular Framework | Acyclic Compounds |
| Substituents | Not Available |
| External Descriptors |
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| External Links | |
| DrugBank ID | Not Available |
| PubChem Compound ID | 23976  |
| KEGG ID | C06268 |
| UniProt ID | Not Available |
| OMIM ID | 271400 |
| ChEBI ID | 28073 |
| BioCyc ID | Not Available |
| CTD ID | D002857 |
| Stitch ID | Chromium |
| PDB ID | Not Available |
| ACToR ID | 7192 |
| Wikipedia Link | http://en.wikipedia.org/wiki/Chromium |
| Physical Properties | |
| Appearance | Not Available |
| Melting Point | 1900 C |
| Solubility | Not Available |
| Predicted LogP | -0.156 |
| Toxicity Profile | |
| Route of Exposure | Oral (R042) ; inhalation (R042); dermal (R042) |
| Mechanism of Action | Hexavalent chromium's carcinogenic effects are caused by its metabolites, pentavalent and trivalent chromium. The DNA damage may be caused by hydroxyl radicals produced during reoxidation of pentavalent chromium by hydrogen peroxide molecules present in the cell. Trivalent chromium may also form complexes with peptides, proteins, and DNA, resulting in DNA-protein crosslinks, DNA strand breaks, DNA-DNA interstrand crosslinks, chromium-DNA adducts, chromosomal aberrations and alterations in cellular signaling pathways. It has been shown to induce carcinogenesis by overstimulating cellular regulatory pathways and increasing peroxide levels by activating certain mitogen-activated protein kinases. It can also cause transcriptional repression by cross-linking histone deacetylase 1-DNA methyltransferase 1 complexes to CYP1A1 promoter chromatin, inhibiting histone modification. Chromium may increase its own toxicity by modifying metal regulatory transcription factor 1, causing the inhibition of zinc-induced metallothionein transcription. (R041, R042, R075, R076, R077) |
| Metabolism | Chromium is absorbed from oral, inhalation, or dermal exposure and distributes to nearly all tissues, with the highest concentrations found in kidney and liver. Bone is also a major storage site and may contribute to long-term retention. Hexavalent chromium's similarity to sulfate and chromate allows it to be transported into cells via sulfate transport mechanisms. Inside the cell, hexavalent chromium is reduced first to pentavalent chromium, then to trivalent chromium by different pathways including ascorbate, glutathione, and nicotinamide adenine dinucleotide. Chromium is almost entirely excreted in the urine. (R041, R042) |
| Toxicity Values | Not Available |
| Lethal Dose | 1 to 3 grams of hexavalent chromium for an adult human. (R331) |
| Carcinogenicity (IARC Classification) | 1, carcinogenic to humans (hexavalent) and 3, not classifiable as to its carcinogenicity to humans (metallic, trivalent). (R264) |
| Uses/Sources | Elemental chromium is used mainly for making steel. Hexavalent chromium is used for chrome plating, dyes and pigments, leather tanning, and wood preserving. (R041, R045) |
| Minimum Risk Level | Intermediate Oral: 0.005 mg/kg/day (Hexavalent chromium) (R260) Chronic Oral: 0.001 mg/kg/day (Hexavalent chromium) (R260) |
| Health Effects | Hexavalent chromium is a known carcinogen. Chronic inhalation especially has been linked to lung cancer. Hexavalent chromium has also been shown to affect reproduction and development. (R041) |
| Symptoms | Breathing hexavalent chromium can cause irritation to the lining of the nose, nose ulcers, runny nose, and breathing problems, such as asthma, cough, shortness of breath, or wheezing. Ingestion of hexavalent chromium causes irritation and ulcers in the stomach and small intestine, as well as anemia. Skin contact can cause skin ulcers. (R042) |
| Treatment | There is no known antidote for chromium poisoning. Exposure is usually handled with symptomatic treatment. (R042) |
| References | |
| General References |
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Targets
1. Mitogen-activated protein kinase 1
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. May play a role in the spindle assembly checkpoint. 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.
Chromium has been shown to induce carcinogenesis by overstimulating cellular regulatory pathways and increasing peroxide levels by activating certain mitogen-activated protein kinases. (R075)UniProt ID: P28482
Gene: MAPK1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R075 — Kim G, Yurkow EJ: Chromium induces a persistent activation of mitogen-activated protein kinases by a redox-sensitive mechanism in H4 rat hepatoma cells. Cancer Res. 1996 May 1;56(9):2045-51.
[8616849 ]
2. Mitogen-activated protein kinase 3
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.
Chromium has been shown to induce carcinogenesis by overstimulating cellular regulatory pathways and increasing peroxide levels by activating certain mitogen-activated protein kinases. (R075)UniProt ID: P27361
Gene: MAPK3
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R075 — Kim G, Yurkow EJ: Chromium induces a persistent activation of mitogen-activated protein kinases by a redox-sensitive mechanism in H4 rat hepatoma cells. Cancer Res. 1996 May 1;56(9):2045-51.
[8616849 ]
3. Histone deacetylase 1
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Component a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.
Chromium can cause transcriptional repression by cross-linking histone deacetylase 1-DNA methyltransferase 1 complexes to CYP1A1 promoter chromatin, inhibiting histone modification. (R076)UniProt ID: Q13547
Gene: HDAC1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R076 — Schnekenburger M, Talaska G, Puga A: Chromium cross-links histone deacetylase 1-DNA methyltransferase 1 complexes to chromatin, inhibiting histone-remodeling marks critical for transcriptional activation. Mol Cell Biol. 2007 Oct;27(20):7089-101. Epub 2007 Aug 6.
[17682057 ]
4. Metal regulatory transcription factor 1
Activates the metallothionein I promoter. Binds to the metal responsive element (MRE).
Chromium may increase its own toxicity by modifying metal regulatory transcription factor 1, causing the inhibition of zinc-induced metallothionein transcription. (R077)UniProt ID: Q14872
Gene: MTF1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R077 — Kimura T: [Molecular mechanism involved in chromium(VI) toxicity] Yakugaku Zasshi. 2007 Dec;127(12):1957-65.
[18057785 ]
5. Cytokine receptor common subunit beta
High affinity receptor for interleukin-3, interleukin-5 and granulocyte-macrophage colony-stimulating factor.
Trivalent chromium may also form complexes with peptides, proteins, and DNA, resulting in DNA-protein crosslinks, DNA strand breaks, DNA-DNA interstrand crosslinks, chromium-DNA adducts, chromosomal aberrations and alterations in cellular signaling pathways. (R042)UniProt ID: P32927
Gene: CSF2RB
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R042 — ATSDR - Agency for Toxic Substances and Disease Registry (2008). Toxicological profile for chromium. U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA). [Link]