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Identification
NameMenadione
Accession NumberDB00170  (NUTR00062)
Typesmall molecule
Groupsapproved, nutraceutical
Description

A synthetic naphthoquinone without the isoprenoid side chain and biological activity, but can be converted to active vitamin K2, menaquinone, after alkylation in vivo. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
2-Methyl-1,4-NaphthalenedioneNot AvailableNot Available
2-Methyl-1,4-naphthoquinoneNot AvailableNot Available
Vitamin K3Not AvailableNot Available
Salts
Name/CAS Structure Properties
Menadiol diphosphate
Thumb Not applicable DBSALT000878
Brand names
NameCompany
SynkaviteNot Available
Brand mixturesNot Available
Categories
CAS number58-27-5
WeightAverage: 172.18
Monoisotopic: 172.0524295
Chemical FormulaC11H8O2
InChI KeyInChIKey=MJVAVZPDRWSRRC-UHFFFAOYSA-N
InChI
InChI=1S/C11H8O2/c1-7-6-10(12)8-4-2-3-5-9(8)11(7)13/h2-6H,1H3
IUPAC Name
2-methyl-1,4-dihydronaphthalene-1,4-dione
SMILES
CC1=CC(=O)C2=CC=CC=C2C1=O
Mass Specshow(8.97 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassAcenes and Derivatives
SubclassNaphthalenes
Direct parentNaphthoquinones
Alternative parentsp-Quinones; p-Benzoquinones; Benzene and Substituted Derivatives; Polyamines
Substituentsp-benzoquinone; quinone; p-quinone; benzene; ketone; polyamine; carbonyl group
Classification descriptionThis compound belongs to the naphthoquinones. These are compounds containing a naphthohydroquinone moiety, which consists of a benzene ring fused to a bezene-1,4-dione (quinone).
Pharmacology
IndicationThe primary known function of vitamin K is to assist in the normal clotting of blood, but it may also play a role in normal bone calcification.
PharmacodynamicsMenadione (Vitamin K3) is a fat-soluble vitamin precursor that is converted into menaquinone in the liver. Vitamin K1 and K2 are the naturally occurring types of vitamin K. The former, which is also known as phylloquinone, is synthesized by plants and can be found in such foods as spinach, broccoli, lettuce, and soybeans. The latter, sometimes alternatively referred to as menaquinone, is primarily produced by bacteria in the anterior part of the gut and the intestines. Vitamin K3, on the other hand, is one of the many manmade versions of vitamin K. Also called menadione, this yellowish, synthetic crystalline substance is converted into the active form of the K2 vitamin inside of the animal body. While a vitamin K deficiency can be dangerous, especially to infants that may easily suffer from extensive hemorrhaging, an overdose can be as equally detrimental. Newborns that are administered too great a dosage of vitamin K3 can suffer from kernicterus, a form of severe brain damage that may produce decreased movement, loss of appetite, seizures, deafness, mental retardation, and even death. This condition is associated with an abnormally high concentration of bilirubin, a bile pigment, in the tissues of the brain, which can be caused by the presence of K3. For this reason, K3 is less often utilized medically than it was in former times.
Mechanism of actionMenadione (vitamin K3) is involved as a cofactor in the posttranslational gamma-carboxylation of glutamic acid residues of certain proteins in the body. These proteins include the vitamin K-dependent coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor), X (Stuart factor), protein C, protein S, protein Zv and a growth-arrest-specific factor (Gas6). In contrast to the other vitamin K-dependent proteins in the blood coagulation cascade, protein C and protein S serve anticoagulant roles. The two vitamin K-dependent proteins found in bone are osteocalcin, also known as bone G1a (gamma-carboxyglutamate) protein or BGP, and the matrix G1a protein or MGP. Gamma-carboxylation is catalyzed by the vitamin K-dependent gamma-carboxylases. The reduced form of vitamin K, vitamin K hydroquinone, is the actual cofactor for the gamma-carboxylases. Proteins containing gamma-carboxyglutamate are called G1a proteins.
AbsorptionVariable and ranges from 10% to 80%
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityMenadione (vitamin K3), which is not used as a nutritional supplemental form of vitamin K for humans, has been reported to cause adverse reactions, including hemolytic anemia. Large doses have also been reported to cause brain damage.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.8265
Caco-2 permeable + 0.8641
P-glycoprotein substrate Non-substrate 0.5245
P-glycoprotein inhibitor I Inhibitor 0.7375
P-glycoprotein inhibitor II Non-inhibitor 0.8743
Renal organic cation transporter Non-inhibitor 0.8027
CYP450 2C9 substrate Non-substrate 0.7596
CYP450 2D6 substrate Non-substrate 0.8924
CYP450 3A4 substrate Non-substrate 0.5705
CYP450 1A2 substrate Inhibitor 0.934
CYP450 2C9 substrate Inhibitor 0.9165
CYP450 2D6 substrate Inhibitor 0.7999
CYP450 2C19 substrate Inhibitor 0.8994
CYP450 3A4 substrate Non-inhibitor 0.7529
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8612
Ames test AMES toxic 0.9108
Carcinogenicity Non-carcinogens 0.9137
Biodegradation Not ready biodegradable 0.7581
Rat acute toxicity 2.7195 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.778
hERG inhibition (predictor II) Non-inhibitor 0.8734
Pharmacoeconomics
Manufacturers
  • Eli lilly and co
Packagers
Dosage formsNot Available
Prices
Unit descriptionCostUnit
Menadione powder5.59USDg
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point107 °CPhysProp
water solubility160 mg/L (at 30 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP2.20HANSCH,C ET AL. (1995)
logS-3.03ADME Research, USCD
Predicted Properties
PropertyValueSource
water solubility5.04e-01 g/lALOGPS
logP1.91ALOGPS
logP1.89ChemAxon
logS-2.5ALOGPS
pKa (strongest acidic)12.94ChemAxon
pKa (strongest basic)-7.2ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count2ChemAxon
hydrogen donor count0ChemAxon
polar surface area34.14ChemAxon
rotatable bond count0ChemAxon
refractivity50.54ChemAxon
polarizability17.64ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
Spectra
References
Synthesis Reference

Joachim U. Schneider, Hans Kiefer, “Menadione choline bisulfite adduct, its preparation and antihemorrhagic compositions.” U.S. Patent US4735969, issued January, 1980.

US4735969
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD02335
KEGG CompoundC05377
PubChem Compound4055
PubChem Substance46505447
ChemSpider3915
BindingDB24778
ChEBI28869
ChEMBLCHEMBL590
Therapeutic Targets DatabaseDNC001501
PharmGKBPA450358
IUPHAR2771
Guide to Pharmacology2771
HETVK3
PDRhealthhttp://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/vit_0267.shtml
WikipediaMenadione
ATC CodesB02BA02
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSshow(52.9 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

1. Vitamin K-dependent gamma-carboxylase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: cofactor

Components

Name UniProt ID Details
Vitamin K-dependent gamma-carboxylase P38435 Details

References:

  1. Wang Z, Wang M, Finn F, Carr BI: The growth inhibitory effects of vitamins K and their actions on gene expression. Hepatology. 1995 Sep;22(3):876-82. Pubmed
  2. Stafford DW: The vitamin K cycle. J Thromb Haemost. 2005 Aug;3(8):1873-8. Pubmed
  3. Presnell SR, Stafford DW: The vitamin K-dependent carboxylase. Thromb Haemost. 2002 Jun;87(6):937-46. Pubmed

2. Vitamin K epoxide reductase complex subunit 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: cofactor

Components

Name UniProt ID Details
Vitamin K epoxide reductase complex subunit 1 Q9BQB6 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Oldenburg J, Bevans CG, Muller CR, Watzka M: Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):347-53. Pubmed
  4. Stafford DW: The vitamin K cycle. J Thromb Haemost. 2005 Aug;3(8):1873-8. Pubmed

3. Vitamin K epoxide reductase complex subunit 1-like protein 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: cofactor

Components

Name UniProt ID Details
Vitamin K epoxide reductase complex subunit 1-like protein 1 Q8N0U8 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Oldenburg J, Bevans CG, Muller CR, Watzka M: Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):347-53. Pubmed
  4. Stafford DW: The vitamin K cycle. J Thromb Haemost. 2005 Aug;3(8):1873-8. Pubmed

4. Prothrombin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Prothrombin P00734 Details

References:

  1. Lee SK, Lee JY, Lee MY, Chung SM, Chung JH: Advantages of calcium green-1 over other fluorescent dyes in measuring cytosolic calcium in platelets. Anal Biochem. 1999 Sep 10;273(2):186-91. Pubmed
  2. Casper HH, Alstad AD, Tacke DB, Johnson LJ, Lloyd WE: Evaluation of vitamin K3 feed additive for prevention of sweet clover disease. J Vet Diagn Invest. 1989 Apr;1(2):116-9. Pubmed
  3. McCarthy DJ, Lindamood C 3rd, Gundberg CM, Hill DL: Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. Toxicol Appl Pharmacol. 1989 Feb;97(2):300-10. Pubmed
  4. Szejtli J, Bolla-Pusztai E, Tardy-Lengyel M, Szabo P, Ferenczy T: Preparation, properties and biological activity of beta-cyclodextrin inclusion complex of menadione. Pharmazie. 1983 Mar;38(3):189-93. Pubmed
  5. Wang Z, Wang M, Finn F, Carr BI: The growth inhibitory effects of vitamins K and their actions on gene expression. Hepatology. 1995 Sep;22(3):876-82. Pubmed

5. Coagulation factor VII

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Coagulation factor VII P08709 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

6. Coagulation factor IX

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Coagulation factor IX P00740 Details

References:

  1. Berkessel A, Guixa M, Schmidt F, Neudorfl JM, Lex J: Highly enantioselective epoxidation of 2-methylnaphthoquinone (vitamin K3) mediated by new cinchona alkaloid phase-transfer catalysts. Chemistry. 2007;13(16):4483-98. Pubmed

7. Coagulation factor X

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Coagulation factor X P00742 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

8. Vitamin K-dependent protein C

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Vitamin K-dependent protein C P04070 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Milgrom E, Diab H, Middleton F, Kane PM: Loss of vacuolar proton-translocating ATPase activity in yeast results in chronic oxidative stress. J Biol Chem. 2007 Mar 9;282(10):7125-36. Epub 2007 Jan 10. Pubmed

9. Vitamin K-dependent protein S

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Vitamin K-dependent protein S P07225 Details

References:

  1. Chai YC, Hendrich S, Thomas JA: Protein S-thiolation in hepatocytes stimulated by t-butyl hydroperoxide, menadione, and neutrophils. Arch Biochem Biophys. 1994 Apr;310(1):264-72. Pubmed
  2. Mallis RJ, Hamann MJ, Zhao W, Zhang T, Hendrich S, Thomas JA: Irreversible thiol oxidation in carbonic anhydrase III: protection by S-glutathiolation and detection in aging rats. Biol Chem. 2002 Mar-Apr;383(3-4):649-62. Pubmed

10. Vitamin K-dependent protein Z

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Vitamin K-dependent protein Z P22891 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

11. Ribosyldihydronicotinamide dehydrogenase [quinone]

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Ribosyldihydronicotinamide dehydrogenase [quinone] P16083 Details

References:

  1. Long DJ 2nd, Iskander K, Gaikwad A, Arin M, Roop DR, Knox R, Barrios R, Jaiswal AK: Disruption of dihydronicotinamide riboside:quinone oxidoreductase 2 (NQO2) leads to myeloid hyperplasia of bone marrow and decreased sensitivity to menadione toxicity. J Biol Chem. 2002 Nov 29;277(48):46131-9. Epub 2002 Sep 25. Pubmed
  2. Kwiek JJ, Haystead TA, Rudolph J: Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines. Biochemistry. 2004 Apr 20;43(15):4538-47. Pubmed
  3. Foster CE, Bianchet MA, Talalay P, Zhao Q, Amzel LM: Crystal structure of human quinone reductase type 2, a metalloflavoprotein. Biochemistry. 1999 Aug 3;38(31):9881-6. Pubmed
  4. Celli CM, Tran N, Knox R, Jaiswal AK: NRH:quinone oxidoreductase 2 (NQO2) catalyzes metabolic activation of quinones and anti-tumor drugs. Biochem Pharmacol. 2006 Jul 28;72(3):366-76. Epub 2006 May 4. Pubmed
  5. Boutin JA, Chatelain-Egger F, Vella F, Delagrange P, Ferry G: Quinone reductase 2 substrate specificity and inhibition pharmacology. Chem Biol Interact. 2005 Feb 10;151(3):213-28. Pubmed

12. NAD(P)H dehydrogenase [quinone] 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
NAD(P)H dehydrogenase [quinone] 1 P15559 Details

References:

  1. Munday R, Smith BL, Munday CM: Effect of butylated hydroxyanisole on the toxicity of 2-hydroxy-1,4-naphthoquinone to rats. Chem Biol Interact. 1999 Feb 12;117(3):241-56. Pubmed
  2. Chiou TJ, Wang YT, Tzeng WF: DT-diaphorase protects against menadione-induced oxidative stress. Toxicology. 1999 Nov 29;139(1-2):103-10. Pubmed
  3. Munday R, Smith BL, Munday CM: Effect of inducers of DT-diaphorase on the toxicity of 2-methyl- and 2-hydroxy-1,4-naphthoquinone to rats. Chem Biol Interact. 1999 Dec 15;123(3):219-37. Pubmed
  4. Ip SP, Yiu HY, Ko KM: Schisandrin B protects against menadione-induced hepatotoxicity by enhancing DT-diaphorase activity. Mol Cell Biochem. 2000 May;208(1-2):151-5. Pubmed
  5. Kishi T, Takahashi T, Mizobuchi S, Mori K, Okamoto T: Effect of dicumarol, a Nad(P)h: quinone acceptor oxidoreductase 1 (DT-diaphorase) inhibitor on ubiquinone redox cycling in cultured rat hepatocytes. Free Radic Res. 2002 Apr;36(4):413-9. Pubmed

13. Osteocalcin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: agonist

Components

Name UniProt ID Details
Osteocalcin P02818 Details

References:

  1. Price PA: Role of vitamin-K-dependent proteins in bone metabolism. Annu Rev Nutr. 1988;8:565-83. Pubmed

1. Xanthine dehydrogenase/oxidase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Xanthine dehydrogenase/oxidase P47989 Details

References:

  1. Yee SB, Pritsos CA: Comparison of oxygen radical generation from the reductive activation of doxorubicin, streptonigrin, and menadione by xanthine oxidase and xanthine dehydrogenase. Arch Biochem Biophys. 1997 Nov 15;347(2):235-41. Pubmed

2. Aldehyde oxidase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Aldehyde oxidase Q06278 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Methylenetetrahydrofolate reductase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Methylenetetrahydrofolate reductase P42898 Details

References:

  1. Vanoni MA, Ballou DP, Matthews RG: Methylenetetrahydrofolate reductase. Steady state and rapid reaction studies on the NADPH-methylenetetrahydrofolate, NADPH-menadione, and methyltetrahydrofolate-menadione oxidoreductase activities of the enzyme. J Biol Chem. 1983 Oct 10;258(19):11510-4. Pubmed
  2. Clark JE, Ljungdahl LG: Purification and properties of 5,10-methylenetetrahydrofolate reductase, an iron-sulfur flavoprotein from Clostridium formicoaceticum. J Biol Chem. 1984 Sep 10;259(17):10845-9. Pubmed

5. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

6. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

7. Cytochrome P450 2A6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2A6 P11509 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:08