Menadione

Last updated
Menadione [1]
Menadione.svg
Menadione-from-xtal-3D-bs-17.png
Names
Preferred IUPAC name
2-Methylnaphthalene-1,4-dione
Other names
Menaphthone; Vitamin K3; β-Methyl-1,4-naphthoquinone; 2-Methyl-1,4-naphthodione; 2-Methyl-1,4-naphthoquinone
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.338 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C11H8O2/c1-7-6-10(12)8-4-2-3-5-9(8)11(7)13/h2-6H,1H3 Yes check.svgY
    Key: MJVAVZPDRWSRRC-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C11H8O2/c1-7-6-10(12)8-4-2-3-5-9(8)11(7)13/h2-6H,1H3
    Key: MJVAVZPDRWSRRC-UHFFFAOYAY
  • O=C\2c1c(cccc1)C(=O)/C(=C/2)C
Properties
C11H8O2
Molar mass 172.183 g·mol−1
AppearanceBright yellow crystals
Density 1.225g/cm3
Melting point 105 to 107 °C (221 to 225 °F; 378 to 380 K)
Insoluble
Pharmacology
B02BA02 ( WHO )
  • Contraindicated (India) [2]
Legal status
  • Generally Rx or withdrawn for human use; approved in animal feed
Hazards
Flash point 113.8 °C (236.8 °F; 386.9 K)
Lethal dose or concentration (LD, LC):
0.5 g/kg (oral, mouse)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Menadione is a natural [3] organic compound with the formula C6H4(CO)2C2H(CH3). It is an analog of 1,4-naphthoquinone with a methyl group in the 2-position. [4] It is sometimes called vitamin K3. Use is allowed as a nutritional supplement in animal feed because of its vitamin K activity.

Contents

Biochemistry

Menadione is converted to vitamin K2 (specifically, MK-4) by the prenyltransferase action of vertebrate UBIAD1. [3] This reaction requires the hydroquinone (reduced) form of K3, menadiol, produced by NQO1. [5]

Menadione is also a circulating form of vitamin K, produced in small amounts (1–5%) after intestinal absorption of K1 and K2. This circulation explains the uneven tissue distribution of MK-4, especially since menadione can penetrate the blood–brain barrier. The cleavage enzyme is yet to be identified. As K3 is known to be toxic in large amounts, researchers speculate that the cleavage process is closely regulated. [5]

Terminology

The compound is variously known as vitamin K3 [6] and provitamin K3. [7] Proponents of the latter name generally argue that the compound is not a real vitamin due to its artificial status (prior to its identification as a circulating intermediate) and its lack of a 3-methyl side chain preventing it from exert all the functions (specifically, it cannot act as a cofactor for GGCX in vitro) [8] of the K vitamins.

Uses

The menadione core is apparent in the structure of vitamin K. Phylloquinone structure.svg
The menadione core is apparent in the structure of vitamin K.

It is an intermediate in the chemical synthesis of vitamin K by first reduction to the diol menadiol, which is susceptible to coupling to the phytol. [9] It is a useful intermediate for organic synthesis in general, as it can be made and modified in a number of ways. [10]

Menadione can be used to generate reactive oxygen species to perform flow cytometry analysis on. It can also be used in microbiological evaluation to, for example, detect fastidious microorganisms. [11]

Animal feed

In the United States, menadione is used in various types of animal feed and is described as having a history of safe use for this purpose, being used in poultry feed prior to 1958. [12]

Low-dose menadione is used as an inexpensive micronutrient for livestock in many countries. Forms of menadione are also included in some pet foods in developed countries as a source of vitamin K. These doses have yielded no reported cases of toxicity from menadione in livestock or pets. Although handling may be hazardous, the European Food Safety Authority found in 2013 that it is an effective source of vitamin K in animal nutrition that does not pose a risk to the environment. [13]

Human use

Despite the fact that it can serve as a precursor to various types of vitamin K, menadione is generally not used as a nutritional supplement in economically developed countries. Menadione for human use at pharmaceutical strength is available in some countries with large lower income populations, such as India. [2] The typical daily dose is 10 mg oral or 2 mg parenteral. [14] It is used in the treatment of hypoprothrombinemia outside of the United States. [2]

Toxicology

Menadione is not believed to be carcinogenic. [15] K3 can cause generation of reactive oxygen species (ROS) by redox cycling and arylation of thiols using its reactive 3-position. [5] ROS generation explains various toxic effects of excessive menadione, including DNA damage and cell death, [15] or on a whole-animal level, cardiac and renal toxicity in rats. [16]

Related Research Articles

<span class="mw-page-title-main">Riboflavin</span> Vitamin and supplement

Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in energy metabolism, cellular respiration, and antibody production, as well as normal growth and development. The coenzymes are also required for the metabolism of niacin, vitamin B6, and folate. Riboflavin is prescribed to treat corneal thinning, and taken orally, may reduce the incidence of migraine headaches in adults.

<span class="mw-page-title-main">Vitamin C</span> Essential nutrient found in citrus fruits and other foods

Vitamin C is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription dietary supplement. As a therapy, it is used to prevent and treat scurvy, a disease caused by vitamin C deficiency.

<span class="mw-page-title-main">Vitamin K</span> Fat-soluble vitamers

Vitamin K is a family of structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation or for controlling binding of calcium in bones and other tissues. The complete synthesis involves final modification of these so-called "Gla proteins" by the enzyme gamma-glutamyl carboxylase that uses vitamin K as a cofactor.

<span class="mw-page-title-main">Pantothenic acid</span> Chemical compound

Pantothenic acid (vitamin B5) is a B vitamin and an essential nutrient. All animals need pantothenic acid in order to synthesize coenzyme A (CoA)—essential for metabolizing fatty acid—and to synthesize and metabolize proteins, carbohydrates, and fats.

Vitamin B<sub>6</sub> Class of chemically related vitamins

Vitamin B6 is one of the B vitamins, and thus an essential nutrient. The term refers to a group of six chemically similar compounds, i.e., "vitamers", which can be interconverted in biological systems. Its active form, pyridoxal 5′-phosphate, serves as a coenzyme in more than 140 enzyme reactions in amino acid, glucose, and lipid metabolism.

<span class="mw-page-title-main">Retinol</span> Chemical compound

Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family that is found in food and used as a dietary supplement. Retinol or other forms of vitamin A are needed for vision, cellular development, maintenance of skin and mucous membranes, immune function and reproductive development. Dietary sources include fish, dairy products, and meat. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xerophthalmia. It is taken by mouth or by injection into a muscle. As an ingredient in skin-care products, it is used to reduce wrinkles and other effects of skin aging.

<span class="mw-page-title-main">Choline</span> Chemical compound and essential nutrient

Choline is an essential nutrient for humans and many other animals, which was formerly classified as a B vitamin . It is a structural part of phospholipids and a methyl donor in metabolic one-carbon chemistry. The compound is related to trimethylglycine in the latter respect. It is a cation with the chemical formula [(CH3)3NCH2CH2OH]+. Choline forms various salts, for example choline chloride and choline bitartrate.

<span class="mw-page-title-main">Cholecalciferol</span> Vitamin D3, a chemical compound

Cholecalciferol, also known as vitamin D3 and colecalciferol, is a type of vitamin D that is made by the skin when exposed to sunlight; it is found in some foods and can be taken as a dietary supplement.

<span class="mw-page-title-main">Phytomenadione</span> Chemical compound

Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin found in food and used as a dietary supplement. It is on the World Health Organization's List of Essential Medicines.

<span class="mw-page-title-main">Menatetrenone</span> Form of vitamin K

Menatetrenone (INN), also known as menaquinone-4 (MK-4), is one of the nine forms of vitamin K2.

<span class="mw-page-title-main">Sodium selenate</span> Chemical compound

Sodium selenate is the inorganic compound with the formula Na
2
SeO
4
, not to be confused with sodium selenite. It exists as the anhydrous salt, the heptahydrate, and the decahydrate. These are white, water-soluble solids. The decahydrate is a common ingredient in multivitamins and livestock feed as a source of selenium. The anhydrous salt is used in the production of some glass. Although the selenates are much more toxic, many physical properties of sodium selenate and sodium sulfate are similar.

<span class="mw-page-title-main">NAD(P)H dehydrogenase (quinone)</span>

In enzymology, a NAD(P)H dehydrogenase (quinone) (EC 1.6.5.2) is an enzyme that catalyzes the chemical reaction

Vitamin K deficiency results from insufficient dietary vitamin K1 or vitamin K2 or both.

<span class="mw-page-title-main">Menadiol</span> Chemical compound

Menadiol is an organic compound with the formula C6H4(COH)2(CH)(CH3). It is formally a derivative of p-hydroquinone. The name vitamin K4 can refer to:

<span class="mw-page-title-main">Naphthoquinone</span> Diketone derived from naphthalene

Naphthoquinones constitute a class of organic compounds structurally related to naphthalene. Two isomers are common for the parent naphthoquinones:

Vitamin K<sub>2</sub> Group of vitamins and bacterial metabolites

Vitamin K2 or menaquinone (MK) is one of three types of vitamin K, the other two being vitamin K1 (phylloquinone) and K3 (menadione). K2 is both a tissue and bacterial product (derived from vitamin K1 in both cases) and is usually found in animal products or fermented foods.

Vitamin B<sub>3</sub> Class of chemically related vitamers

Vitamin B3, colloquially referred to as niacin, is a vitamin family that includes three forms, or vitamers: niacin (nicotinic acid), nicotinamide (niacinamide), and nicotinamide riboside. All three forms of vitamin B3 are converted within the body to nicotinamide adenine dinucleotide (NAD). NAD is required for human life and people are unable to make it within their bodies without either vitamin B3 or tryptophan. Nicotinamide riboside was identified as a form of vitamin B3 in 2004.

<span class="mw-page-title-main">Nivalenol</span> Type of mycotoxin

Nivalenol (NIV) is a mycotoxin of the trichothecene group. In nature it is mainly found in fungi of the Fusarium species. The Fusarium species belongs to the most prevalent mycotoxin producing fungi in the temperate regions of the northern hemisphere, therefore making them a considerable risk for the food crop production industry.

<span class="mw-page-title-main">4-Amino-2-methyl-1-naphthol</span> Chemical compound

4-Amino-2-methyl-1-naphthol is a menadione analog. Its water-soluble hydrochloride (HCl) salt is often called vitamin K5. The HCl salt has been used as a medicine for vitamin K deficiency under tradenames such as Synkamin, which was sold by Parke-Davis, but has since been discontinued.

Megavitamin-B6 syndrome is a collection of symptoms that can result from chronic supplementation, or acute overdose, of vitamin B6. While it is also known as hypervitaminosis B6, vitamin B6 toxicity and vitamin B6 excess, megavitamin-b6 syndrome is the name used in the ICD-10.

References

  1. The Merck Index , 11th Edition, 5714
  2. 1 2 3 "Menadione drug information". DrugsUpdate India.
  3. 1 2 Hirota, Yoshihisa; Tsugawa, Naoko; Nakagawa, Kimie; Suhara, Yoshitomo; Tanaka, Kiyoshi; Uchino, Yuri; Takeuchi, Atsuko; Sawada, Natsumi; Kamao, Maya; Wada, Akimori; Okitsu, Takashi (2013-11-15). "Menadione (vitamin K3) is a catabolic product of oral phylloquinone (vitamin K1) in the intestine and a circulating precursor of tissue menaquinone-4 (vitamin K2) in rats". The Journal of Biological Chemistry. 288 (46): 33071–33080. doi: 10.1074/jbc.M113.477356 . ISSN   1083-351X. PMC   3829156 . PMID   24085302.
  4. Castro FA, Mariani D, Panek AD, Eleutherio EC, Pereira MD (2008). Fox (ed.). "Cytotoxicity mechanism of two naphthoquinones (menadione and plumbagin) in Saccharomyces cerevisiae". PLOS ONE. 3 (12): e3999. Bibcode:2008PLoSO...3.3999C. doi: 10.1371/journal.pone.0003999 . PMC   2600608 . PMID   19098979.
  5. 1 2 3 Shearer, Martin J.; Newman, Paul (March 2014). "Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis". Journal of Lipid Research. 55 (3): 345–362. doi: 10.1194/jlr.R045559 . ISSN   0022-2275. PMC   3934721 . PMID   24489112.
  6. Scott GK, Atsriku C, Kaminker P, Held J, Gibson B, Baldwin MA, Benz CC (September 2005). "Vitamin K3 (menadione)-induced oncosis associated with keratin 8 phosphorylation and histone H3 arylation". Molecular Pharmacology. 68 (3): 606–15. doi:10.1124/mol.105.013474. PMID   15939799. S2CID   19076885.
  7. "Vitamin K". Linus Pauling Institute. 2014-04-22. Retrieved 2021-01-28.
  8. Buitenhuis, HC; Soute, BA; Vermeer, C (16 May 1990). "Comparison of the vitamins K1, K2 and K3 as cofactors for the hepatic vitamin K-dependent carboxylase". Biochimica et Biophysica Acta (BBA) - General Subjects. 1034 (2): 170–5. doi:10.1016/0304-4165(90)90072-5. PMID   2112953.
  9. Weber F, Rüttimann A (2012). "Vitamin K". Ullmann's Encyclopedia Of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.o27_o08. S2CID   86263542.
  10. de Souza, AS; Ribeiro, RCB; Costa, DCS; Pauli, FP; Pinho, DR; de Moraes, MG; da Silva, FC; Forezi, LDSM; Ferreira, VF (2022). "Menadione: a platform and a target to valuable compounds synthesis". Beilstein Journal of Organic Chemistry. 18: 381–419. doi:10.3762/bjoc.18.43. PMC   9039524 . PMID   35529893.
  11. "Menadione". Sigma-Aldrich. Retrieved 2 February 2023.
  12. "Vitamin K Substances and Animal Feed". FDA. 2 April 2021.
  13. EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) (January 2014). "Scientific Opinion on the safety and efficacy of vitamin K3 (menadione sodium bisulphite and menadione nicotinamide bisulphite) as a feed additive for all animal species". EFSA Journal. 12 (1): 3532. doi: 10.2903/j.efsa.2014.3532 .
  14. "Menadione (B02BA02)". WHOCC - ATC/DDD Index.
  15. 1 2 Hassan, Ghada S. (2013). "Menadione". Profiles of Drug Substances, Excipients and Related Methodology. Vol. 38. pp. 227–313. doi:10.1016/B978-0-12-407691-4.00006-X. ISBN   9780124076914. PMID   23668406. S2CID   242264898.
  16. Chiou, TJ; Zhang, J; Ferrans, VJ; Tzeng, WF (31 December 1997). "Cardiac and renal toxicity of menadione in rat". Toxicology. 124 (3): 193–202. doi:10.1016/s0300-483x(97)00162-5. PMID   9482121.