Menadione

Menadione is converted to vitamin K₂ (specifically, MK-4) by the prenyltransferase action of vertebrate UBIAD1. This reaction requires the hydroquinone (reduced) form of K₃, menadiol, produced by NQO1.{{Cite journal|last1=Shearer|first1=Martin J.|last2=Newman|first2=Paul|date=March 2014|title=Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis|journal=Journal of Lipid Research|volume=55|issue=3|pages=345–362|doi=10.1194/jlr.R045559 |doi-access=free |issn=0022-2275|pmc=3934721|pmid=24489112}}

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.

The compound is variously known as vitamin K₃{{cite journal|vauthors=Scott GK, Atsriku C, Kaminker P, Held J, Gibson B, Baldwin MA, Benz CC|date=September 2005|title=Vitamin K3 (menadione)-induced oncosis associated with keratin 8 phosphorylation and histone H3 arylation|journal=Molecular Pharmacology|volume=68|issue=3|pages=606–15|doi=10.1124/mol.105.013474|pmid=15939799|s2cid=19076885}} and provitamin K₃.{{Cite web|date=2014-04-22|title=Vitamin K|url=https://lpi.oregonstate.edu/mic/vitamins/vitamin-K|access-date=2021-01-28|website=Linus Pauling Institute|language=en}} 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 exerting all the functions (specifically, it cannot act as a cofactor for GGCX in vitro){{cite journal |last1=Buitenhuis |first1=HC |last2=Soute |first2=BA |last3=Vermeer |first3=C |title=Comparison of the vitamins K1, K2 and K3 as cofactors for the hepatic vitamin K-dependent carboxylase. |journal=Biochimica et Biophysica Acta (BBA) - General Subjects |date=16 May 1990 |volume=1034 |issue=2 |pages=170–5 |doi=10.1016/0304-4165(90)90072-5 |pmid=2112953}} of the K vitamins.

File:Phylloquinone structure.svg.]]

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.{{cite book | first1 = Fritz | last1 = Weber | first2 = August | last2 = Rüttimann | name-list-style = vanc | chapter = Vitamin K | title = Ullmann's Encyclopedia Of Industrial Chemistry | date = 2012 | publisher = Wiley-VCH | location = Weinheim | doi = 10.1002/14356007.o27_o08 | s2cid = 86263542 }} It is a useful intermediate for organic synthesis in general, as it can be made and modified in a number of ways.{{cite journal |last1=de Souza |first1=AS |last2=Ribeiro |first2=RCB |last3=Costa |first3=DCS |last4=Pauli |first4=FP |last5=Pinho |first5=DR |last6=de Moraes |first6=MG |last7=da Silva |first7=FC |last8=Forezi |first8=LDSM |last9=Ferreira |first9=VF |title=Menadione: a platform and a target to valuable compounds synthesis. |journal=Beilstein Journal of Organic Chemistry |date=2022 |volume=18 |pages=381–419 |doi=10.3762/bjoc.18.43 |pmid=35529893 |pmc=9039524}}

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.{{cite web |title=Menadione |url=https://www.sigmaaldrich.com/US/en/product/sigma/m5625 |website=Sigma-Aldrich |access-date=2 February 2023}}

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.{{Cite journal|url=https://www.fda.gov/animal-veterinary/safe-feed/vitamin-k-substances-and-animal-feed|archive-url=https://web.archive.org/web/20190930201801/https://www.fda.gov/animal-veterinary/safe-feed/vitamin-k-substances-and-animal-feed|url-status=dead|archive-date=September 30, 2019|title=Vitamin K Substances and Animal Feed|journal=FDA|date=2 April 2021}}

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.{{cite journal | author = EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) | title = 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. | journal = EFSA Journal | date = January 2014 | volume = 12 | issue = 1 | pages = 3532 | doi = 10.2903/j.efsa.2014.3532 | doi-access = free }}

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. The typical daily dose is 10 mg oral or 2 mg parenteral.{{cite web |title=Menadione (B02BA02) |url=https://www.whocc.no/atc_ddd_index/?code=B02BA02 |website=WHOCC - ATC/DDD Index}} It is used in the treatment of hypoprothrombinemia outside of the United States.{{cite web |title=Menadione drug information |url=https://www.drugsupdate.com/generic/view/1153/Menadione |website=DrugsUpdate India}}

Menadione is not believed to be carcinogenic. K3 can cause generation of reactive oxygen species (ROS) by redox cycling and arylation of thiols using its reactive 3-position. ROS generation explains various toxic effects of excessive menadione, including DNA damage and cell death,{{cite book |last1=Hassan |first1=Ghada S. |chapter=Menadione |chapter-url=https://www.sciencedirect.com/science/article/pii/B978012407691400006X |title=Profiles of Drug Substances, Excipients, and Related Methodology |series=Profiles of Drug Substances, Excipients and Related Methodology |date=2013 |volume=38 |pages=227–313 |doi=10.1016/B978-0-12-407691-4.00006-X|pmid=23668406 |isbn=9780124076914 |s2cid=242264898 }} or on a whole-animal level, cardiac and renal toxicity in rats.{{cite journal |last1=Chiou |first1=TJ |last2=Zhang |first2=J |last3=Ferrans |first3=VJ |last4=Tzeng |first4=WF |title=Cardiac and renal toxicity of menadione in rat. |journal=Toxicology |date=31 December 1997 |volume=124 |issue=3 |pages=193–202 |doi=10.1016/s0300-483x(97)00162-5 |pmid=9482121|bibcode=1997Toxgy.124..193C }}

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Category:1,4-Naphthoquinones

Category:Vitamin K