Menadione

Biochemistry

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

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.

Terminology

The compound is variously known as vitamin K3 and provitamin K3. 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) of the K vitamins.

Derivatives

The following are more water-soluble derivatives of menadione. They are also included in the term "vitamin K3":

• Menadione sodium bisulfite or "menadione sodium bisulfite complex" (IUPAC name sodium;2-methyl-1,4-dioxo-3H-naphthalene-2-sulfonate) is the sodium salt of the 2-sulfonate of menadione (menadione bisulfide).
• Menadione nicotinamide bisulfite is a salt of nicotinamide and the 2-sulfonate of menadione. It has dual niacin and vitamin K activity in animal feed.

Uses

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. It is a useful intermediate for organic synthesis in general, as it can be made and modified in a number of ways.

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.

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.

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.

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 and the Philippines. The typical daily dose is 10 mg oral or 2 mg parenteral. It is used in the treatment of hypoprothrombinemia outside of the United States.

Toxicology

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, or on a whole-animal level, cardiac and renal toxicity in rats.

References

References

1. (1989). "[[The Merck Index]]". Merck & Co., Inc..
2. (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.
3. (2008). "Cytotoxicity mechanism of two naphthoquinones (menadione and plumbagin) in Saccharomyces cerevisiae". PLOS ONE.
4. (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.
5. (November 2010). "Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme". Nature.
6. (September 2005). "Vitamin K3 (menadione)-induced oncosis associated with keratin 8 phosphorylation and histone H3 arylation". Molecular Pharmacology.
7. (2014-04-22). "Vitamin K".
8. (16 May 1990). "Comparison of the vitamins K1, K2 and K3 as cofactors for the hepatic vitamin K-dependent carboxylase.". Biochimica et Biophysica Acta.
9. "Recommendations for Use of Menadione Sodium Bisulfite Complex (MSBC) in Animal Feed". Association of American Feed Control Officials (AAFCO).
10. (2012). "Ullmann's Encyclopedia Of Industrial Chemistry". Wiley-VCH.
11. (2022). "Menadione: a platform and a target to valuable compounds synthesis.". Beilstein Journal of Organic Chemistry.
12. "Menadione".
13. (2 April 2021). "Vitamin K Substances and Animal Feed". U.S. Food and Drug Administration.
14. (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.
15. "Menadione Sodium Bisulfite 10 mg tablet (Medione) package insert". U.S. Food and Drug Administration.
16. "Menadione (B02BA02)".
17. "Menadione drug information".
18. (2013). "Profiles of Drug Substances, Excipients, and Related Methodology".
19. (31 December 1997). "Cardiac and renal toxicity of menadione in rat.". Toxicology.