Inositol

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 Template:Chem2; the molecule has a ring of six carbon atoms, each with a hydrogen atom and a hydroxyl 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 aldoses 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.<ref name=liyu2021/> 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.<ref>Template:Cite journal</ref> In other tissues, it mediates cell signal transduction in response to a variety of hormones, neurotransmitters, and growth factors and participates in osmoregulation.<ref name="parthasarthy">Template:Cite book</ref> In most mammalian cells the concentrations of myo-inositol are 5 to 500 times greater inside cells than outside them.<ref name="pmid33755975"/>

A 2023 meta-analysis found that inositol is a safe and effective treatment in the management of polycystic ovary syndrome (PCOS).<ref name="pcos2023"/> However, there is only evidence of very low quality for its efficacy in increasing fertility for IVF in women with PCOS.<ref name=showell2018>Template:Cite journal</ref>

The other naturally occurring stereoisomers of cyclohexane-1,2,3,4,5,6-hexol are scyllo-, muco-, [[1D-chiro-inositol|Template:Small-chiro]]-, [[L-chiro-inositol|Template:Small-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

myo-Inositol was first isolated from muscle extracts by Johanes Joseph Scherer (1814–1869) in 1850.<ref name=liyu2021/> 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.<ref name=reyn1993/>

Chemical properties

myo-Inositol is a meso compound, meaning it is optically inactive because it has a plane of symmetry.<ref name=maju2006/> 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.<ref name=liyu2021/>

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.<ref>Template:Cite book</ref>

Physiological roles

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

In humans, myo-Inositol is synthesized de novo but Template:Small-chiro-inositol is not.<ref name="pmid33755975"/> 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.<ref name="parthasarthy"/>

At the peripheral level, myo-inositol is converted to Template:Small-chiro-inositol by a specific epimerase. Only a minor fraction of myo-inositol is converted into Template:Small-chiro-inositol.<ref name="pmid33755975"/> The activity of this epimerase is insulin dependent, causing a reduction of Template:Small-chiro-inositol in muscle, fat, and liver when there is insulin resistance.<ref name="carlomagno">Template:Cite journal</ref><ref name="pmid33755975"/> Template:Small-chiro-inositol reduces the conversion of testosterone to estrogen, thereby increases the levels of testosterone and worsening PCOS.<ref name="pmid33755975">Template:Cite journal</ref>

Phytic acid in plants

File:Phytic acid.svg

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.<ref name="phytochemicals">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="CAST">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref>

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.<ref name="foods"/> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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

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:

• Insulin signal transduction<ref name="Larner J 2002 47–60">Template:Cite journal</ref>
• Cytoskeleton assembly
• Nerve guidance (epsin)
• Intracellular calcium (Ca²⁺) concentration control<ref>Template:Cite journal</ref>
• Cell membrane potential maintenance<ref name="pmid9017197">Template:Cite journal</ref>
• Breakdown of fats<ref name="pmid3103610">Template:Cite journal</ref>
• Gene expression<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref>Template:Cite book</ref>

'myo-Inositol has very low toxicity, with a reported LD₅₀ 10,000 mg/kg body weight (oral) in rats.<ref name=liyu2021/>

Industrial uses

Explosives industry

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.<ref>Template:Cite news</ref> Today, inositol nitrate is used to gelatinize nitrocellulose in many modern explosives and solid rocket propellants.<ref>Template:Cite book</ref>

Road salt

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.<ref>Template:Cite journal</ref>

Research and clinical applications

Trichotillomania

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.<ref>Template:Cite journal</ref>

Other illnesses

D-chiro-inositol is an important messenger molecule in insulin signaling.<ref name="pmid29793496">Template:Cite journal</ref> Inositol supplementation has been shown to significantly decrease triglycerides and LDL cholesterol in patients with metabolic diseases.<ref name="pmid29793496"/>

myo-Inositol is important for thyroid hormone synthesis.<ref name="pmid34040582"/> Depletion of myo-inositol may predispose to development of hypothyroidism.<ref name="pmid34040582"/> Patients with hypothyroidism have a higher demand for myo-inositol than healthy subjects.<ref name="pmid34040582">Template:Cite journal</ref>

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).<ref>Template:Cite journal</ref> Myo-inositol helps prevent neural tube defects with particular efficacy in combination with folic acid.<ref>Template:Cite journal</ref>

Inositol is considered a safe and effective treatment for polycystic ovary syndrome (PCOS).<ref name="pcos2023">Template:Cite journal</ref> It works by increasing insulin sensitivity, which helps to improve ovarian function and reduce hyperandrogenism.<ref>Template:Cite journal</ref> It is also shown to reduce the risk of metabolic disease in women with PCOS.<ref>Template:Cite journal</ref> In addition, thanks to its role as FSH second messenger, myo-inositol is effective in restoring FSH/LH ratio and menstrual cycle regularization.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In contrast, Template:Small-chiro-inositol can impair oocyte quality in a dose-dependent manner.<ref>Template:Cite journalTemplate:Expression of Concern</ref> The high level of DCI seems to be related to elevated insulin levels retrieved in about 70% of PCOS women.<ref>Template:Cite journal</ref> In this regard, insulin stimulates the irreversible conversion of myo-inositol to Template:Small-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.<ref name="carlomagno"/> 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 Template:Small-chiro-inositol in healthy subjects is 40:1 of myo- and Template:Small-chiro-inositol respectively.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Use as a cutting agent

Inositol has been used as an adulterant or cutting agent for many illegal drugs, such as cocaine, methamphetamine, and sometimes heroin,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite magazine</ref><ref>Template:Citation</ref>

Nutritional sources

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.<ref name='foods'>Template:Cite journal</ref> Foods containing the highest concentrations of myo-inositol and its compounds include fruits, beans, grains, and nuts.<ref name='foods'/> Fruits in particular, especially oranges and cantaloupe, contain the highest amounts of myo-inositol.<ref name='sugar alcohol'>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

myo-Inositol can also be found as an ingredient in energy drinks,<ref>Template:Cite journal</ref> either in conjunction with or as a substitute for glucose.<ref>Template:Cite magazine</ref>

In humans, myo-inositol is naturally made from glucose-6-phosphate through enzymatic dephosphorylation.<ref name='sugar alcohol'/>

Production

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.<ref name=liyu2021/>

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).<ref name=liyu2021/> 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.<ref name=liyu2021/>

External links

• Inositol MS Spectrum
• Inositol bound to proteins in the PDB