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myo-Inositol[1]
myo-Inositol
myo-Inositol
myo-Inositol
myo-Inositol
Names
IUPAC name
myo-Inositol
Systematic IUPAC name
(1R,2S,3r,4R,5S,6s)-Cyclohexane-1,2,3,4,5,6-hexol
Other names
cis-1,2,3,5-trans-4,6-Cyclohexanehexol
Cyclohexanehexol
Mouse antialopecia factor
Nucite
Phaseomannite
Phaseomannitol
Rat antispectacled eye factor
Scyllite (for the isomer scyllo-inositol)
Vitamin B8
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.027.295 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C6H12O6/c7-1-2(8)4(10)6(12)5(11)3(1)9/h1-12H/t1-,2-,3-,4+,5-,6- checkY
    Key: CDAISMWEOUEBRE-GPIVLXJGSA-N checkY
  • InChI=1/C6H12O6/c7-1-2(8)4(10)6(12)5(11)3(1)9/h1-12H/t1-,2-,3-,4+,5-,6-
    Key: CDAISMWEOUEBRE-GPIVLXJGBG
  • O[C@@H]1[C@@H](O)[C@H](O)[C@H](O)[C@H](O)[C@H]1O
Properties
C6H12O6
Molar mass 180.16 g/mol
Density 1.752 g/cm3
Melting point 225 to 227 °C (437 to 441 °F; 498 to 500 K)
Thermochemistry[2]
−1329.3 kJ/mol
−2747 kJ/mol
Pharmacology
A11HA07 (WHO)
Hazards
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineFlammability 0: Will not burn. E.g. waterInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
1
0
0
Flash point 143 °C (289 °F; 416 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

In biochemistry, medicine, and related sciences, inositol generally refers to myo-inositol (formerly meso-inositol), the most important stereoisomer of the chemical compound cyclohexane-1,2,3,4,5,6-hexol. Its formula is C6H12O6; the molecule has a ring of six carbon atoms, each with a hydrogen atom and a hydroxy group (–OH). In myo-inositol, two of the hydroxyls, neither adjacent nor opposite, lie above the respective hydrogens relative to the mean plane of the ring.

The compound is a carbohydrate, specifically a sugar alcohol (as distinct from simple sugars like glucose) with half the sweetness of sucrose (table sugar). It is one of the most ancient components of living beings with multiple functions in eukaryotes, including structural lipids and secondary messengers.[3] A human kidney makes about two grams per day from glucose, but other tissues synthesize it too. The highest concentration is in the brain, where it plays an important role in making other neurotransmitters and some steroid hormones bind to their receptors.[4] In other tissues, it mediates cell signal transduction in response to a variety of hormones, neurotransmitters, and growth factors and participates in osmoregulation.[5] In most mammalian cells the concentrations of myo-inositol are 5 to 500 times greater inside cells than outside them.[6]

A 2023 meta-analysis found that inositol is a safe and effective treatment in the management of polycystic ovary syndrome (PCOS).[7] However, there is only evidence of very low quality for its efficacy in increasing fertility for IVF in women with PCOS.[8]

The other naturally occurring stereoisomers of cyclohexane-1,2,3,4,5,6-hexol are scyllo-, muco-, D-chiro-, L-chiro-, and neo-inositol, although they occur in minimal quantities compared to myo-inositol. The other possible isomers are allo-, epi-, and cis-inositol.

History

[edit]

myo-Inositol was first isolated from muscle extracts by Johanes Joseph Scherer (1814–1869) in 1850.[3] It was formerly called meso-inositol to distinguish it from the chiro- isomers. However, since all other isomers are meso (non-chiral) compounds, the name myo-inositol is now preferred (myo- being a medical prefix for "muscle").

Inositol was once considered a member of the vitamin B complex, namely vitamin B8 before the discovery that it is made naturally in the human body, and therefore cannot be a vitamin or essential nutrient.[9]

Chemical properties

[edit]

myo-Inositol is a meso compound, meaning it is optically inactive because it has a plane of symmetry.[10] It is a white crystalline powder, relatively stable in the air. It is highly soluble in water, slightly soluble in glacial acetic acid, ethanol, glycol, and glycerin, but insoluble in chloroform and ether.[3]

In its most stable conformation, the myo-inositol isomer assumes the chair conformation, which moves the maximum number of hydroxyls to the equatorial position, where they are farthest apart from each other. In this conformation, the natural myo isomer has a structure in which five of the six hydroxyls (the first, third, fourth, fifth, and sixth) are equatorial, whereas the second hydroxyl group is axial.[11]

Physiological roles

[edit]

Myo-Inositol plays an important role as the structural basis for a number of secondary messengers in eukaryotic cells, the various inositol phosphates. In addition, inositol serves as an important component of the structural lipids phosphatidylinositol (PI) and its various phosphates, the phosphatidylinositol phosphate (PIP) lipids.

Biosynthesis

[edit]

In humans, myo-Inositol is synthesized de novo but D-chiro-inositol is not.[6] myo-Inositol is synthesized from glucose 6-phosphate (G6P) in two steps. First, G6P is isomerised by an inositol-3-phosphate synthase enzyme (for example, ISYNA1) to myo-inositol 1-phosphate, which is then dephosphorylated by an inositol monophosphatase enzyme (for example, IMPA1) to give free myo-inositol. In humans, most inositol is synthesized in the kidneys, followed by testicles, typically in amounts of a few grams per day.[5]

At the peripheral level, myo-inositol is converted to D-chiro-inositol by a specific epimerase. Only a minor fraction of myo-inositol is converted into D-chiro-inositol.[6] The activity of this epimerase is insulin dependent, causing a reduction of D-chiro-inositol in muscle, fat, and liver when there is insulin resistance.[12][6] D-chiro-inositol reduces the conversion of testosterone to estrogen, thereby increases the levels of testosterone and worsening PCOS.[6]

Phytic acid in plants

[edit]
2D-structure of phytic acid
Inositolhexaphosphate, or phytic acid

Inositol hexaphosphate, also called phytic acid or IP6, is a phytochemical and the principal storage form of phosphorus in many plant tissues, especially bran and seed.[13] Phosphorus and inositol in phytate form are not generally bioavailable to non-ruminant animals because these animals lack the digestive enzyme phytase required to remove the phosphate groups. Ruminants readily digest phytate because of the phytase produced by microorganisms in the rumen.[14] Moreover, phytic acid also chelates important minerals such as calcium, magnesium, iron, and zinc, making them unabsorbable, and contributing to mineral deficiencies in people whose diets rely highly on bran and seeds for their mineral intake, such as occurs in developing countries.[15][16] Because of this, phytic acid is considered as an antinutrient.

Inositol penta- (IP5), tetra- (IP4), and triphosphate (IP3) are also called "phytates".

Inositol or its phosphates and associated lipids are found in many foods, in particular fruit, especially cantaloupe and oranges.[17] In plants, the hexaphosphate of inositol, phytic acid or its salts, the phytates, serve as phosphate stores in seed, for example in nuts and beans.[18] Phytic acid also occurs in cereals with high bran content. Phytate is, however, not directly bioavailable to humans in the diet, since it is not digestible. Some food preparation techniques partly break down phytates to change this. However, inositol in the form of phospholipids, as found in certain plant-derived substances such as lecithins, is well absorbed and relatively bioavailable.

Biological function

[edit]

Inositol, phosphatidylinositol, and some of their mono- and polyphosphates function as secondary messengers in a number of intracellular signal transduction pathways. They are involved in a number of biological processes, including:

In one important family of pathways, phosphatidylinositol 4,5-bisphosphate (PIP2) is stored in cellular membranes until it is released by any of a number of signalling proteins and transformed into various secondary messengers, for example diacylglycerol and inositol trisphosphate.[25]

'myo-Inositol has very low toxicity, with a reported LD50 10,000 mg/kg body weight (oral) in rats.[3]

Industrial uses

[edit]

Explosives industry

[edit]

At the 1936 meeting of the American Chemical Society, professor Edward Bartow of the University of Iowa presented a commercially viable means of extracting large amounts of inositol from the phytic acid naturally present in waste corn. As a possible use for the chemical, he suggested 'inositol nitrate' as a more stable alternative to nitroglycerin.[26] Today, inositol nitrate is used to gelatinize nitrocellulose in many modern explosives and solid rocket propellants.[27]

Road salt

[edit]

When plants are exposed to increasing concentrations of road salt, the plant cells become dysfunctional and undergo apoptosis, leading to inhibited growth. Inositol pretreatment could reduce these effects.[28]

Research and clinical applications

[edit]

Trichotillomania

[edit]

High doses of inositol have been explored for treatment of trichotillomania (compulsive hair-pulling) and related disorders, but no definitive evidence points to its effectiveness.[29]

Other illnesses

[edit]

D-chiro-inositol is an important messenger molecule in insulin signaling.[30] Inositol supplementation has been shown to significantly decrease triglycerides and LDL cholesterol in patients with metabolic diseases.[30]

myo-Inositol is important for thyroid hormone synthesis.[31] Depletion of myo-inositol may predispose to development of hypothyroidism.[31] Patients with hypothyroidism have a higher demand for myo-inositol than healthy subjects.[31]

Inositol should not be routinely implemented for the management of preterm babies who have or are at a risk of infant respiratory distress syndrome (RDS).[32] Myo-inositol helps prevent neural tube defects with particular efficacy in combination with folic acid.[33]

Inositol is considered a safe and effective treatment for polycystic ovary syndrome (PCOS).[7] It works by increasing insulin sensitivity, which helps to improve ovarian function and reduce hyperandrogenism.[34] It is also shown to reduce the risk of metabolic disease in women with PCOS.[35] In addition, thanks to its role as FSH second messenger, myo-inositol is effective in restoring FSH/LH ratio and menstrual cycle regularization.[36] myo-Inositol's role as FSH second messenger leads to a correct ovarian follicle maturation and consequently to a higher oocyte quality. Improving the oocyte quality in both women with or without PCOS, myo-inositol can be considered as a possible approach for increasing the chance of success in assisted reproductive technologies.[37][38] In contrast, D-chiro-inositol can impair oocyte quality in a dose-dependent manner.[39] The high level of DCI seems to be related to elevated insulin levels retrieved in about 70% of PCOS women.[40] In this regard, insulin stimulates the irreversible conversion of myo-inositol to D-chiro-inositol causing a drastic reduction of myo-inositol. myo-Inositol depletion is particularly damaging to ovarian follicles because it is involved in FSH signaling, which is impaired due to myo-inositol depletion.[12] Recent evidence reports a faster improvement of the metabolic and hormonal parameters when these two isomers are administered in their physiological ratio. The plasmatic ratio of myo-inositol and D-chiro-inositol in healthy subjects is 40:1 of myo- and D-chiro-inositol respectively.[41] The use of the 40:1 ratio shows the same efficacy of myo-inositol alone but in a shorter time. In addition, the physiological ratio does not impair oocyte quality.[42]

The use of inositols in PCOS is gaining more importance, and an efficacy higher than 70% with a strong safety profile is reported. On the other hand, about 30% of patients could show as inositol-resistant.[43] New evidence regarding PCOS aetiopathogenesis describes an alteration in the species and the quantity of each strain characterizing the normal gastrointestinal flora. This alteration could lead to chronic, low-level inflammation and malabsorption.[44] A possible solution could be represented by the combination of myo-inositol and α-lactalbumin. This combination shows a synergic effect in increasing myo-inositol absorption.[45] A recent study reported that the myo-inositol and α-lactalbumin combination increases myo-inositol plasmatic content in inositol-resistant patients with a relative improvement of hormonal and metabolic parameters.[46]

Use as a cutting agent

[edit]

Inositol has been used as an adulterant or cutting agent for many illegal drugs, such as cocaine, methamphetamine, and sometimes heroin,[47] probably because of its solubility, powdery texture, or reduced sweetness (50%) compared to more common sugars.

Inositol is also used as a stand-in film prop for cocaine in filmmaking.[48][49]

Nutritional sources

[edit]

myo-Inositol is naturally present in a variety of foods, although tables of food composition do not always distinguish between lecithin, the relatively bioavailable lipid form and the biounavailable phytate/phosphate form.[17] Foods containing the highest concentrations of myo-inositol and its compounds include fruits, beans, grains, and nuts.[17] Fruits in particular, especially oranges and cantaloupe, contain the highest amounts of myo-inositol.[50] It is also present in beans, nuts, and grains, however, these contain large amounts of myo-inositol in the phytate form, which is not bioavailable without transformation by phytase enzymes. Bacillus subtilis, the microorganism which produces the fermented food natto, produces phytase enzymes that may convert phytic acid to a more bioavailable form of inositol polyphosphate in the gut.[51] Additionally, Bacteroides species in the gut secrete vesicles containing an active enzyme which converts the phytate molecule into bioavailable phosphorus and inositol polyphosphate, which is an important signaling molecule in the human body.[52]

myo-Inositol can also be found as an ingredient in energy drinks,[53] either in conjunction with or as a substitute for glucose.[54]

In humans, myo-inositol is naturally made from glucose-6-phosphate through enzymatic dephosphorylation.[50]

Production

[edit]

As of 2021, the main industrial process for the production of myo-inositol (mostly in China and Japan) started with phytate (IP6) extracted from the soaking water resulting from corn and rice bran processing. After purification, the phytate is hydrolized, and myo-inositol is separated by crystallization.[3]

Another route is microbial fermentation of carbohydrates by various organisms, such as the fungus Neurospora crassa (Beadle and Tatum, 1945), Candida boidini (Shirai et al., 1997), Saccharomyces cerevisiae (Culbertson et al., 1976), Escherichia coli (Hansen, 1999).[3] Alternatively, enzyme extracts from microbial cultures can be used in vitro to obtain myo-inositol from various substrates, including glucose, sucrose, starch, xylose, and amylose.[3]

References

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[edit]
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Inositol

View on Grokipedia
from Grokipedia
Inositol is a group of nine stereoisomers of hexahydroxycyclohexane, a carbocyclic sugar alcohol with the general molecular formula C₆H₁₂O₆, where myo-inositol is the most abundant isomer in mammalian tissues and the primary biologically active form, while D-chiro-inositol is another key isomer utilized in therapeutic supplementation. Myo-inositol features a cyclohexane ring with hydroxyl groups on each carbon, adopting a chair conformation that facilitates its incorporation into cellular structures and signaling molecules. As a vitamin-like nutrient, it functions primarily as a precursor to phosphatidylinositol, a key component of cell membranes, and inositol phosphates, which serve as second messengers in pathways regulating insulin action, calcium mobilization, and gene expression. In living organisms, inositol is ubiquitous, derived biosynthetically from glucose and widely distributed in plants and animals, where it supports osmoregulation, growth, and metabolic homeostasis. Humans obtain inositol through dietary intake from sources such as whole grains, beans, nuts (including almonds and walnuts), fruits like cantaloupe and citruses, and vegetables, with typical daily consumption ranging from 0.5 to 1 gram in Western diets. Endogenous production occurs in the kidneys and brain via the enzyme myo-inositol-3-phosphate synthase, converting glucose-6-phosphate, ensuring physiological needs are met even under low dietary conditions. Beyond its structural roles, inositol exhibits diverse physiological effects, including enhancement of insulin sensitivity and reduction of hyperandrogenism in polycystic ovary syndrome (PCOS). Supplementation with myo-inositol (typically 4 g/day) improves insulin sensitivity, menstrual regularity, ovulation, and egg quality in women with PCOS, serving as an alternative to metformin with better tolerability. Combination with D-chiro-inositol in a 40:1 myo-inositol to D-chiro-inositol ratio (e.g., 4 g myo-inositol + 100 mg D-chiro-inositol) is often preferred, as clinical evidence and guidelines indicate it more effectively restores ovarian balance, hormone levels, and metabolic parameters than either isomer alone. While myo-inositol primarily supports insulin signaling and ovarian function, D-chiro-inositol alone or in high doses may impair ovarian function and egg quality. It also contributes to lipid metabolism as a lipotropic agent, preventing fat accumulation in the liver, with clinical studies demonstrating benefits in non-alcoholic fatty liver disease (NAFLD) through reduced liver fat accumulation, lowered serum ALT and AST levels, and improved cardiometabolic factors such as insulin resistance and lipid profiles. It shows promise in managing metabolic syndrome through improvements in glucose tolerance and inflammatory markers. Research highlights its safety as a nutraceutical, with supplementation doses up to 18 grams per day tolerated without significant adverse effects, underscoring its potential in preventive and therapeutic nutrition.

Chemical Properties

Structure and Isomers

Inositol is a cyclohexanehexol with the molecular C₆H₁₂O₆, characterized by a six-membered carbon ring where each carbon atom bears a hydroxyl group. This allows for multiple stereoisomeric forms due to the presence of six chiral centers on the ring. The possible stereoisomers of inositol total nine, arising from the various configurations of the hydroxyl groups around the ring; seven of these are meso compounds, which are achiral because of an internal plane of , while the remaining two constitute a pair of that exhibit optical activity. Among these, myo-inositol is the predominant and most biologically significant , accounting for approximately 90% of the total inositol in human tissues. In its stable chair conformation, myo-inositol features five hydroxyl groups in equatorial positions and one axial hydroxyl group at the C2 position, conferring a plane of that renders it meso. Key examples include D-chiro-inositol, one of the chiral enantiomers lacking a plane of , which displays optical activity and has hydroxyl group orientations that differ from the meso forms, specifically with axial hydroxyls at positions C1 and C2 in the standard numbering (or equivalent in chair flip). Scyllo-inositol, a meso , adopts a highly stable chair conformation with all six hydroxyl groups in equatorial positions, maximizing and minimizing steric interactions. The non-meso forms, such as the chiro-inositols, are optically active due to their enantiomeric nature, rotating plane-polarized light in opposite directions for the D and L variants, whereas all meso s, including myo- and scyllo-inositol, are optically inactive.

Physical and Chemical Characteristics

Inositol, particularly its predominant myo-isomer, presents as an odorless white crystalline solid at room temperature. Its density is 1.75 g/cm³, reflecting a compact molecular packing typical of polyols. The compound melts at 225–227 °C, above which it decomposes without boiling under standard conditions. Myo-inositol exhibits high in , reaching up to 140 g/L at 25 °C, which facilitates its role in aqueous biological environments. In contrast, it shows low solubility in most organic solvents, such as (approximately 2.5 g/L at 25 °C) and negligible solubility in non-polar solvents like or . Chemically, inositol functions as a non-reducing due to the absence of a free , rendering it under conditions that degrade reducing sugars. It demonstrates good and oxidative stability, remaining resistant to mild oxidation but reacting with strong oxidizing agents; it is combustible but non-flammable under normal handling. The six hydroxyl groups have pKa values around 12.6, indicating weak acidity and limited at physiological , though these groups readily undergo to form inositol phosphates. Spectroscopic methods are essential for identification. In infrared (IR) spectroscopy, myo-inositol shows a broad O-H stretching band at approximately 3350 cm⁻¹ and C-O stretching vibrations between 1050 and 1150 cm⁻¹, confirming its structure. (¹H NMR) in D₂O reveals characteristic multiplets for the methine protons between δ 3.10 and 3.60 ppm, with a distinct triplet at δ 3.28 ppm for the axial proton at C-2. Among isomers, myo-inositol displays greater aqueous compared to scyllo-inositol, whose molar solubility is roughly 8.6 times lower, attributed to differences in hydrogen bonding efficiency. Scyllo-inositol also exhibits enhanced conformational stability in polar solvents due to its higher , minimizing steric interactions.

History

Discovery and Isolation

In 1850, German chemist and physician Johann Joseph Scherer isolated a novel compound from extracts of muscle tissue, naming it inositol after the Greek word "inos," referring to muscle or sinew, due to its taste reminiscent of a . This marked the first identification of inositol as a distinct substance, initially termed "muscle " for its organ-specific occurrence and properties. Subsequent purification efforts advanced the understanding of inositol's chemical identity. In 1887, French chemist Léon Maquenne obtained crystalline inositol from plant leaves and established its as C₆H₁₂O₆, confirming its structural relation to carbohydrates while distinguishing it from glucose. Maquenne later refined the isolation using boiled horse urine as a source, though this method drew local complaints owing to the odor. The 1940s brought confirmation of inositol's stereochemical diversity through the systematic studies of Swiss Th. Posternak in 1942, who elucidated the configurations of its nine possible isomers and identified myo-inositol as the predominant form in biological systems. Early extraction methods from plant materials focused on abundant sources like corn steep liquor and rice bran, where inositol exists primarily as (inositol hexaphosphate). These involved acid of phytate to liberate free inositol, followed by , , and recrystallization, enabling scalable isolation for research by the mid-20th century.

Recognition as a Biochemical Compound

In the 1920s and 1930s, inositol began to gain attention as a potential essential nutrient due to its role as a growth factor in microorganisms and animals. In 1940, D.W. Woolley demonstrated that inositol was required for optimal growth and prevention of alopecia in mice fed a purified diet, prompting its classification as a member of the vitamin B complex, specifically vitamin B8. However, experiments in the 1940s revealed that mammals, including mice and rats, could synthesize inositol endogenously from glucose, leading to its retraction as an essential vitamin by the mid-20th century. By the 1950s, research shifted toward inositol's integration into cellular structures, particularly its presence in phospholipids. In 1953, Lowell E. Hokin and Mabel R. Hokin reported the "Hokin effect," observing that stimulation in pigeon slices rapidly increased the incorporation of radioactive into , highlighting its dynamic role in cellular responses. This discovery laid foundational insights into inositol lipids' involvement in , later contributing to Nobel Prize-recognized advancements in understanding receptor-mediated signaling pathways. The nomenclature of inositol evolved alongside its biochemical characterization. Coined in 1850 by Johann Joseph Scherer from the Greek word "inos" (meaning muscle or sinew), reflecting its initial isolation from muscle tissue, the term "inositol" was standardized to specify stereoisomers. By the mid-20th century, myo-inositol emerged as the predominant biologically active form, distinguished from other isomers like scyllo- and chiro-inositol through structural analyses. A pivotal milestone occurred in the 1970s with Robert H. Michell's elucidation of inositol phosphates' functions. In his 1975 review, Michell proposed that receptor activation at the cell surface triggered the hydrolysis of , generating inositol phosphates as second messengers essential for calcium mobilization and cellular signaling. This framework integrated prior observations into a cohesive model of inositol's biochemical significance, influencing decades of subsequent research.

Biosynthesis and Production

Biosynthetic Pathways

In living organisms, myo-inositol is synthesized de novo through a conserved two-step enzymatic pathway beginning with glucose-6-phosphate. The rate-limiting first step is catalyzed by myo-inositol-3-phosphate synthase (MIPS), which isomerizes and cyclizes glucose-6-phosphate to myo-inositol-3-phosphate in an NAD⁺-dependent reaction. The second step involves of myo-inositol-3-phosphate to free myo-inositol by the inositol monophosphatase (IMPase). This pathway can be summarized by the following reactions: Glucose-6-phosphate+NAD+→MIPSmyo-Inositol-3-phosphate+NADH+H+\text{Glucose-6-phosphate} + \text{NAD}^+ \xrightarrow{\text{MIPS}} \text{myo-Inositol-3-phosphate} + \text{NADH} + \text{H}^+
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