Tmic
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Record Information
Version2.0
Creation Date2010-05-03 20:06:17 UTC
Update Date2014-12-24 20:26:27 UTC
Accession NumberT3D3727
Identification
Common NameAlternariol
ClassSmall Molecule
DescriptionAlternariol is found in mushrooms. Alternariol occurs in mycelium of Alternaria tenuis responsible for alternaria cone disorder in hops and fruit spot on papaya (Carica papaya) and Passiflora species.Alternariol is a toxic metabolite of Alternaria fungi. It is an important contaminant in cereals and fruits. Alternariol belongs to the family of Isocoumarins and Derivatives. These are polycyclic compounds containing an isochromane which bears a ketone at the carbon C1.
Compound Type
  • Ester
  • Food Toxin
  • Fungal Toxin
  • Metabolite
  • Mycotoxin
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
Synonyms
Synonym
1-Methyl-3,7,9-trihydroxy-6H-Dibenzo(b,D)pyran-6-one
3,4',5-Trihydroxy-6'-methyldibenzo-a-pyrone
3,7,9-Trihydroxy-1-methyl-6H-benzo[c]chromen-6-one
3,7,9-Trihydroxy-1-methyl-6H-dibenzo(b,D)pyran-6-one
3,7,9-Trihydroxy-1-methyl-6H-Dibenzo[b,D]pyran-6-one
3,7,9-Trihydroxy-1-methyl-6H-dibenzo[b,D]pyran-6-one, 9CI
Alternariol 3,4',5-Trihydroxy-6'-methyl-dibenzo[a]pyrone
Alternariol from alternaria SP.
AOH
Chemical FormulaC14H10O5
Average Molecular Mass258.226 g/mol
Monoisotopic Mass258.053 g/mol
CAS Registry Number641-38-3
IUPAC Name3,7,9-trihydroxy-1-methyl-6H-benzo[c]chromen-6-one
Traditional Namealternariol
SMILESCC1=CC(O)=CC2=C1C1=C(C(=O)O2)C(O)=CC(O)=C1
InChI IdentifierInChI=1S/C14H10O5/c1-6-2-7(15)5-11-12(6)9-3-8(16)4-10(17)13(9)14(18)19-11/h2-5,15-17H,1H3
InChI KeyInChIKey=CEBXXEKPIIDJHL-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as coumarins and derivatives. These are polycyclic aromatic compounds containing a 1-benzopyran moiety with a ketone group at the C2 carbon atom (1-benzopyran-2-one).
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassCoumarins and derivatives
Sub ClassNot Available
Direct ParentCoumarins and derivatives
Alternative Parents
Substituents
  • Coumarin
  • Isocoumarin
  • Benzopyran
  • 1-benzopyran
  • 2-benzopyran
  • 1-hydroxy-4-unsubstituted benzenoid
  • 1-hydroxy-2-unsubstituted benzenoid
  • Pyranone
  • Pyran
  • Benzenoid
  • Heteroaromatic compound
  • Vinylogous acid
  • Lactone
  • Oxacycle
  • Polyol
  • Organoheterocyclic compound
  • Organooxygen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organic oxygen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point350°C
Boiling PointNot Available
SolubilityNot Available
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.23 g/LALOGPS
logP2.49ALOGPS
logP3.18ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)7.63ChemAxon
pKa (Strongest Basic)-4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area86.99 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity67.92 m³·mol⁻¹ChemAxon
Polarizability25.14 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0bu3-0190000000-ab90d95f25f23b1c1d4dView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-11b9-2202900000-492de99142b0a0d1994cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - DI-ESI-qTof , Positivesplash10-0a4i-0090000000-49a9dc87e5577f9cc6aaView in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0a4i-0290000000-913a843eb1fbe0ab9082View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0a4i-0490000000-4c5e72338325be202711View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-0090000000-95b8c497427d61e438f4View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a4i-0090000000-51f692a816351a0b1b59View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-05mo-1290000000-46150e766500f30952d8View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0090000000-353041795899e746b989View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-0090000000-7411b04aa0ed4ee2981dView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-066u-1390000000-b231ee41769f3f5f967aView in MoNA
Toxicity Profile
Route of ExposureOral, dermal, inhalation, and parenteral (contaminated drugs). (5)
Mechanism of ToxicityAlternariol is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
MetabolismAlternariol is metabolized by microsomes in the liver, preferentially at aromatic positions. The products of aromatic hydroxylation are either catechols or hydroquinones, which may form reactive semiquinones and quinones or undergo redox cycling. (4)
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesAlternariol is an altertoxin, which is a toxic metabolite of Alternaria fungi. It is an important contaminant in cereals, vegetables, and fruits, as well as in the ground, on wood or walls. (7, 1)
Minimum Risk LevelNot Available
Health EffectsAcute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.
SymptomsSymptoms of low dose exposure include excessive salivation and eye-watering. Acute dose symptoms include severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Hypertension, hypoglycemia, anxiety, headache, tremor and ataxia may also result.
TreatmentIf the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDHMDB30831
PubChem Compound ID5359485
ChEMBL IDCHEMBL519982
ChemSpider ID4514301
KEGG IDC16838
UniProt IDNot Available
OMIM ID
ChEBI ID64983
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkAlternariol
References
Synthesis ReferenceNot Available
MSDST3D3727.pdf
General References
  1. Fehr M, Pahlke G, Fritz J, Christensen MO, Boege F, Altemoller M, Podlech J, Marko D: Alternariol acts as a topoisomerase poison, preferentially affecting the IIalpha isoform. Mol Nutr Food Res. 2009 Apr;53(4):441-51. doi: 10.1002/mnfr.200700379. [18727009 ]
  2. Brugger EM, Wagner J, Schumacher DM, Koch K, Podlech J, Metzler M, Lehmann L: Mutagenicity of the mycotoxin alternariol in cultured mammalian cells. Toxicol Lett. 2006 Jul 14;164(3):221-30. Epub 2006 Feb 7. [16464542 ]
  3. Lehmann L, Wagner J, Metzler M: Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells. Food Chem Toxicol. 2006 Mar;44(3):398-408. Epub 2005 Sep 27. [16194592 ]
  4. Pfeiffer E, Schebb NH, Podlech J, Metzler M: Novel oxidative in vitro metabolites of the mycotoxins alternariol and alternariol methyl ether. Mol Nutr Food Res. 2007 Mar;51(3):307-16. [17340575 ]
  5. Peraica M, Domijan AM: Contamination of food with mycotoxins and human health. Arh Hig Rada Toksikol. 2001 Mar;52(1):23-35. [11370295 ]
  6. Yannai, Shmuel. (2004) Dictionary of food compounds with CD-ROM: Additives, flavors, and ingredients. Boca Raton: Chapman & Hall/CRC.
  7. Wikipedia. Alternariol. Last Updated 12 April 2010. [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Poly(a) rna binding
Specific Function:
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component ARNTL/BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the ARNTL/BMAL1 promoter.
Gene Name:
TOP1
Uniprot ID:
P11387
Molecular Weight:
90725.19 Da
References
  1. Fehr M, Pahlke G, Fritz J, Christensen MO, Boege F, Altemoller M, Podlech J, Marko D: Alternariol acts as a topoisomerase poison, preferentially affecting the IIalpha isoform. Mol Nutr Food Res. 2009 Apr;53(4):441-51. doi: 10.1002/mnfr.200700379. [18727009 ]
  2. Brugger EM, Wagner J, Schumacher DM, Koch K, Podlech J, Metzler M, Lehmann L: Mutagenicity of the mycotoxin alternariol in cultured mammalian cells. Toxicol Lett. 2006 Jul 14;164(3):221-30. Epub 2006 Feb 7. [16464542 ]
  3. Lehmann L, Wagner J, Metzler M: Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells. Food Chem Toxicol. 2006 Mar;44(3):398-408. Epub 2005 Sep 27. [16194592 ]
2. DNA
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Fehr M, Pahlke G, Fritz J, Christensen MO, Boege F, Altemoller M, Podlech J, Marko D: Alternariol acts as a topoisomerase poison, preferentially affecting the IIalpha isoform. Mol Nutr Food Res. 2009 Apr;53(4):441-51. doi: 10.1002/mnfr.200700379. [18727009 ]
  2. Brugger EM, Wagner J, Schumacher DM, Koch K, Podlech J, Metzler M, Lehmann L: Mutagenicity of the mycotoxin alternariol in cultured mammalian cells. Toxicol Lett. 2006 Jul 14;164(3):221-30. Epub 2006 Feb 7. [16464542 ]
  3. Lehmann L, Wagner J, Metzler M: Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells. Food Chem Toxicol. 2006 Mar;44(3):398-408. Epub 2005 Sep 27. [16194592 ]
General Function:
Ubiquitin binding
Specific Function:
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes. May play a role in regulating the period length of ARNTL/BMAL1 transcriptional oscillation (By similarity).
Gene Name:
TOP2A
Uniprot ID:
P11388
Molecular Weight:
174383.88 Da
References
  1. Fehr M, Pahlke G, Fritz J, Christensen MO, Boege F, Altemoller M, Podlech J, Marko D: Alternariol acts as a topoisomerase poison, preferentially affecting the IIalpha isoform. Mol Nutr Food Res. 2009 Apr;53(4):441-51. doi: 10.1002/mnfr.200700379. [18727009 ]
  2. Brugger EM, Wagner J, Schumacher DM, Koch K, Podlech J, Metzler M, Lehmann L: Mutagenicity of the mycotoxin alternariol in cultured mammalian cells. Toxicol Lett. 2006 Jul 14;164(3):221-30. Epub 2006 Feb 7. [16464542 ]
  3. Lehmann L, Wagner J, Metzler M: Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells. Food Chem Toxicol. 2006 Mar;44(3):398-408. Epub 2005 Sep 27. [16194592 ]
General Function:
Protein kinase c binding
Specific Function:
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks.
Gene Name:
TOP2B
Uniprot ID:
Q02880
Molecular Weight:
183265.825 Da
References
  1. Fehr M, Pahlke G, Fritz J, Christensen MO, Boege F, Altemoller M, Podlech J, Marko D: Alternariol acts as a topoisomerase poison, preferentially affecting the IIalpha isoform. Mol Nutr Food Res. 2009 Apr;53(4):441-51. doi: 10.1002/mnfr.200700379. [18727009 ]
  2. Brugger EM, Wagner J, Schumacher DM, Koch K, Podlech J, Metzler M, Lehmann L: Mutagenicity of the mycotoxin alternariol in cultured mammalian cells. Toxicol Lett. 2006 Jul 14;164(3):221-30. Epub 2006 Feb 7. [16464542 ]
  3. Lehmann L, Wagner J, Metzler M: Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells. Food Chem Toxicol. 2006 Mar;44(3):398-408. Epub 2005 Sep 27. [16194592 ]
General Function:
Serine hydrolase activity
Specific Function:
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.
Gene Name:
ACHE
Uniprot ID:
P22303
Molecular Weight:
67795.525 Da
References
  1. Lehmann L, Wagner J, Metzler M: Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells. Food Chem Toxicol. 2006 Mar;44(3):398-408. Epub 2005 Sep 27. [16194592 ]
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. Lehmann L, Wagner J, Metzler M: Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells. Food Chem Toxicol. 2006 Mar;44(3):398-408. Epub 2005 Sep 27. [16194592 ]
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. Lehmann L, Wagner J, Metzler M: Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells. Food Chem Toxicol. 2006 Mar;44(3):398-408. Epub 2005 Sep 27. [16194592 ]