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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/02/19 16:47:31」(JST)

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Dicoumarol (INN) or dicumarol (USAN) is a naturally occurring anticoagulant that functions as a functional vitamin K depleter (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases.

Dicoumarol is a natural chemical substance of combined plant and fungal origin. It is a derivative of coumarin, a bitter-tasting but sweet-smelling substance made by plants that does not itself affect coagulation, but which is (classically) transformed in mouldy feeds or silages by a number of species of fungi, into active dicoumarol. Dicoumarol does affect coagulation, and was discovered in mouldy wet sweet-clover hay, as the cause of a naturally occurring bleeding disease in cattle.^[1] See warfarin for a more detailed discovery history.

Identified in 1940, dicoumarol became the prototype of the 4-hydroxycoumarin derivative anticoagulant drug class. Dicoumarol itself, for a short time, was employed as a medicinal anticoagulant drug, but since the mid-1950s has been replaced by its simpler derivative warfarin, and other 4-hydroxycoumarin drugs.

It is given orally, and it acts within two days.

Mechanism of action

Like all 4-hydroxycoumarin drugs it is a competitive inhibitor of vitamin K epoxide reductase, an enzyme that recycles vitamin K, thus causing depletion of active vitamin K in blood. This prevents the formation of the active form of prothrombin and several other coagulant enzymes. These compounds are not direct antagonists (in the pharmaceutical sense) of vitamin K itself, but rather act to deplete reduced vitamin K in tissues. For this reason, vitamin K antagonizes their effect (rather than the reverse), and this has led to the loose terminology of vitamin K antagonism. Administration of vitamin K is therefore the antidote for dicoumarol toxicity. The action and toxicity of the drug and the antidote effectiveness are measured with the prothrombin time (PT) blood test.

Uses

Dicoumarol was used, along with heparin, for the treatment of deep venous thrombosis. Unlike heparin, this class of drugs may be used for months or years.

Poisoning

Overdose results in serious, sometimes fatal uncontrolled hemorrhage.^[2]

Footnotes

^ Nicole Kresge, Robert D. Simoni and Robert L. Hill (2005-02-25). "Sweet clover disease and warfarin review". Jbc.org. Retrieved 2012-09-26.
^ Duff, I. F.; Shull, W. H. (1949). "Fatal Hemorrhage in Dicumarol® Poisoning". Journal of the American Medical Association 139 (12): 762–6. doi:10.1001/jama.1949.02900290008003. PMID 18112552. edit

References

Cullen J, Hinkhouse M, Grady M, Gaut A, Liu J, Zhang Y, Weydert C, Domann F, Oberley L (2003). "Dicumarol inhibition of NADPH: quinone oxidoreductase induces growth inhibition of pancreatic cancer via a superoxide-mediated mechanism.". Cancer Res 63 (17): 5513–20. PMID 14500388.
Mironov A, Colanzi A, Polishchuk R, Beznoussenko G, Mironov A, Fusella A, Di Tullio G, Silletta M, Corda D, De Matteis M, Luini A (2004). "Dicumarol, an inhibitor of ADP-ribosylation of CtBP3/BARS, fragments golgi non-compact tubular zones and inhibits intra-golgi transport.". Eur J Cell Biol 83 (6): 263–79. doi:10.1078/0171-9335-00377. PMID 15511084.
Abdelmohsen K, Stuhlmann D, Daubrawa F, Klotz L (2005). "Dicumarol is a potent reversible inhibitor of gap junctional intercellular communication.". Arch Biochem Biophys 434 (2): 241–7. doi:10.1016/j.abb.2004.11.002. PMID 15639223.
Thanos C, Liu Z, Reineke J, Edwards E, Mathiowitz E (2003). "Improving relative bioavailability of dicumarol by reducing particle size and adding the adhesive poly(fumaric-co-sebacic) anhydride.". Pharm Res 20 (7): 1093–100. doi:10.1023/A:1024474609667. PMID 12880296. ]

External links

DDB 30166

English Journal

Inhibitory effects and oxidative target site of dibutyl phthalate on Karenia brevis.

Li FM1, Wu M2, Yao Y2, Zheng X3, Zhao J2, Wang ZY2, Xing BS4.
Chemosphere.Chemosphere.2015 Aug;132:32-9. doi: 10.1016/j.chemosphere.2015.01.051. Epub 2015 Mar 13.
The inhibitory action and possible damage mechanism of dibutyl phthalate (DBP) on the red tide algae Karenia brevis were investigated. The results showed that the algae experienced oxidative stress after exposure to 5mgL(-1) DBP. Malondialdehyde (MDA) peaked after 72h, with a value approximately 2.3
PMID 25770834

Dicoumarol: a drug which hits at least two very different targets in vitamin K metabolism.

Timson DJ1.
Current drug targets.Curr Drug Targets.2015 Jul 22. [Epub ahead of print]
Dicoumarol, a symmetrical biscoumarin can be considered as the "parent" of the widely used anticoagulant drug, warfarin. The discovery of dicoumarol's bioactive properties resulted from an investigation into a mysterious cattle disease in the 1940s. It was then developed as a pharmaceutical, but was
PMID 26201483

HIV-1 Rev downregulates Tat expression and viral replication via modulation of NAD(P)H:quinine oxidoreductase 1 (NQO1).

Lata S1, Ali A2, Sood V3, Raja R2, Banerjea AC2.
Nature communications.Nat Commun.2015 Jun 10;6:7244. doi: 10.1038/ncomms8244.
HIV-1 gene expression and replication largely depend on the regulatory proteins Tat and Rev, but it is unclear how the intracellular levels of these viral proteins are regulated after infection. Here we report that HIV-1 Rev causes specific degradation of cytoplasmic Tat, which results in inhibition
PMID 26059226

Japanese Journal

Iron deficiency induces changes in riboflavin secretion and the mitochondrial electron transport chain in hairy roots of Hyoscyamus albus.

Higa Ataru,Mori Yuko,Kitamura Yoshie
Journal of plant physiology 167(11), 870-878, 2010-07-15
… In order to examine which elements of the mitochondrial electron transport chain might be involved, the effects of the respiratory inhibitors, barbiturate, dicoumarol, malonic acid, antimycin, KCN and salicylhydroxamic acid (SHAM) were investigated. … Riboflavin secretion was decreased, in concert with TTC-reducing activity, by dicoumarol, antimycin and KCN, but not by SHAM. …
NAID 120002243315

In Vitro Inhibitory Effects of Pulvinic Acid Derivaties Isolated from Chinese Edible Mushrooms, Boletus calopus and Suillus bovinus, on Cytochrome P450 Activity

Huang Yu-Ting,Onose Jun-ichi,Abe Naoki [他],YOSHIKAWA Kunie
Bioscience, biotechnology, and biochemistry 73(4), 855-860, 2009-04-23
… Variegatic acid (<B>2</B>) and xerocomic acid (<B>3</B>) were effective inhibitors, comparable to cimetidine, dicoumarol, erythromycin, safrole, and uniconazole. …
NAID 10027539731

Dicoumarol による癌特異的シスプラチン感受性増強効果についての検討(第93回日本泌尿器科学会総会)

松井喜之,渡部淳,西山博之,川西博晃,伊藤将彰,高橋毅,東新,小川修
日本泌尿器科學會雜誌 96(2), 320, 2005-03-05
NAID 110004039256

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Dicoumarol
Systematic (IUPAC) name
	3,3'-methylenebis(4-hydroxy-2H-chromen-2-one)
Clinical data
MedlinePlus	a605015
Legal status	US: ℞-only; Withdrawn from us market;
Pharmacokinetic data
Protein binding	plasmatic proteins
Metabolism	hepatic
Excretion	faeces, urine
Identifiers
CAS number	66-76-2
ATC code	B01AA01
PubChem	CID 653
DrugBank	DB00266
ChemSpider	10183330
UNII	7QID3E7BG7
KEGG	D03798
ChEBI	CHEBI:4513
ChEMBL	CHEMBL1466
NIAID ChemDB	016070
Chemical data
Formula	C19H12O6
Molecular mass	336.295 g/mol
	SMILES c1ccc2c(c1)c(c(c(=O)o2)Cc3c(c4ccccc4oc3=O)O)O;
	InChI InChI=1S/C19H12O6/c20-16-10-5-1-3-7-14(10)24-18(22)12(16)9-13-17(21)11-6-2-4-8-15(11)25-19(13)23/h1-8,20-21H,9H2 ; Key:DOBMPNYZJYQDGZ-UHFFFAOYSA-N ;
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英: dicumarol、dicoumarol
同: ビスヒドロキシクマリン bishydroxycoumarin, 4-hydroxydicoumarin

[1] Nicole Kresge, Robert D. Simoni and Robert L. Hill (2005-02-25). "Sweet clover disease and warfarin review". Jbc.org. Retrieved 2012-09-26.

[2] Duff, I. F.; Shull, W. H. (1949). "Fatal Hemorrhage in Dicumarol® Poisoning". Journal of the American Medical Association 139 (12): 762–6. doi:10.1001/jama.1949.02900290008003. PMID 18112552. edit

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dicoumarol