Garlic

Last Updated: December 22 2022

Garlic (Allium sativum) is a food and is commonly taken as a supplement. It has anti-inflammatory effects and can improve cardiovascular health.

Garlic is most often used for.



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1.

Sources and Composition

1.1

Sources

Allium sativum (of the Allioideae subfamily) is a food product known as Garlic in the same genus as onion plants (allium) alongside some other common food products such as onion, garlic, chive, leek, and rakkyo. The genera contains above 500 different plants, and while in the past it was placed in the Liliaceae family it now resides as the largest genera in the Amaryllidaceae family.[1][2][3] There are some other vegetables that bear the name of garlic but are different species, and this includes Tulbaghia violacea (Sweet Garlic) and Allium ursinum (Wild Garlic).[4]

There are two main varieties (variants or var.) of garlic named either ophioscorodon (full designation is Allium sativum var. ophioscorodon), which is also called hardnecked garlic or purple striped garlic, and sativum (literally Allium sativum var. sativum), which is also called creole garlic or artichoke garlic.[1][5] Other variants include Voghiera (large bulbed Italian variety),[6] Spring Garlic (pinkish and with a milder taste),[7]

Garlic is a plant known as Allium sativum, which is a plant related to both onions and leeks, and it can be found in a wide variety of 'variants' (variations of the typical vegetable), which are specifically cultivated for their taste properties or yield

Garlic appears to have historical usage for being a medicinal food product as the Babylonians, Egyptians, Phoenicians, Vikings, Chinese, Greeks, and Romans have reported usage of garlic[8][9] for intestinal disorders, flatulence, worms, respiratory infections, skin diseases, wounds, symptoms of aging, and a variety of other purposes (as a general prophylactic).[8] It can be traced back about 6,000 years with known cultivation 5,000 years ago in India for medicinal purposes and recorded usage in China (3,000 years ago) and Egypt (1,550 BC)[10][11] and appears to have been given to slaves to increase their ability to do more labour[10] and was given to Grecian athletes and is sometimes referred to as the first performance enhancing supplement.[11]

It also appears to be quite a popular supplement, with survey research in 2002 (USA) suggesting that 3.76% of the population used garlic supplements[12] and in Australia (2007) this number was 10.7%, with 29.8% of those using garlic supplements in Australia (3.18% of the population) using it for the treatment of colds.[13]

Traditional usage of garlic tends to be catered towards intestinal health and longevity, but it has a fair bit of traditional usage in bolstering the defenses of the body (this can be interpreted as either the immune system, anti-infective properties, or actual physical enhancement) and there are limited reports of its cardiovascular benefits

1.2

Composition

When looking at the garlic bulb itself (overall vegetable product) it tends to contain:

  • A water content of around 65%[10]
  • A carbohydrate content of around 28% (which is mostly fructans)[10]
  • Protein at around 2% (mostly alliinase and glycoproteins) and 1.2% free amino acids[10]
  • 2.3% organosulfur compounds (commonly seen as the main bioactives)[10]
  • 1.5% dietary fiber[10]

Garlic bioactives are somewhat unique in the vegetable, as there are two main groups of molecules that exist in the actual clove prior to processing; alliin (S-allylcysteine sulfoxide) and the Glutamyl-S-allylcysteine molecules. These two classes are some of the organosulfur compounds mentioned above, and aside from being relatively balanced (unless otherwise processed) they make up the majority of the organosulfurs.[14]

When the clove is mechanically disturbed (chewing, slicing, crushing) then alliin turns into allicin via alliinase and then allicin spontaneously creates all manner of bioactives and gives off some hydrogen sulfide (H2S) in the process. When the clove ages, the Glutamyl-S-allylcystiene molecules slowly lose their glutamyl moieties and it increases levels of S-allylcysteine (SAC) among some other similar cysteine prodrugs.

image

Garlic contains two main classes of molecules, which spontaneously form a wide variety of bioactives. This includes alliin (main sulfur containing compound in fresh garlic), which converts into allicin via the above pathway, and the glutamyl-S-allylcysteine, which gradually form S-allylcysteine during the aging process (which can then form SAMC and SMC)

image

The known bioactives of garlic are:

  • Alliin (S-allylcysteine sulfoxide) as one a pool of bioactives at 10mg/g fresh weight and 30mg/g dry weight of raw garlic[14] and of which 70-80% degrades into Allicin (Diallyl thiosulfinate; not present in the garlic initially[8][15]) and is then further degraded into the Diallyl sulfides, the Ajoene molecule[16] and the dithiin class of cyclic molecules[17]
  • The Glutamyl-S-allyl-L-cysteine class of molecules (second initial pool of bioactives) including γ-glutamyl-S-allyl-L-cysteine and γ-glutamyl-S-(trans-1-propenyl)-L-cysteine, two molecules present in garlic in high levels alongside low levels of γ-glutamyl-S-allyl-mercapto-L-cysteine and S-allylcystiene (SAC);[18] SAC content increases during aging of garlic from 200µg/g to 7,200µg/g[19] and is seen as the main bioactive of 'aged' garlic[20]
  • The diallyl sulfides, which include; diallyl sulfide, diallyl disulfide (DADS), diallyl trisulfide (DATS or Allitridi), and diallyl tetrasulfide (DATTS),[21][22][23] which are seen as the main bioactives of garlic oil and main derivatives of allicin;[22] letting allicin sit for 20 hours results in DADS (66.7%), DATS (14.6%), DAS (13.3%) and diallyl tetrasulfide (5.4%)[24] with higher polysulfides being of sparse quantities;[25] diallyl sulfides are seen as the main metabolite(s) of allicin
  • A cyclical form of alliin known as cycloalliin[26] and the fat soluble[16] cyclical derivatives of allicin[17] known as vinyldithiins such as 1,2-vinyldithiin;[27] these derivates are more sparse than the diallyl sulfides[28]
  • Ajoene ((E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide), one of the stable end products of alliin degradation[29] and made from allicin S-thiolation and 2-propenesulfenic acid addition and again less prominent than diallyl sulfides[28]
  • Allylmercaptane (AM) and allylmethyl sulfide (AMS), which are produced from DADS after oral ingestion[30] and oxidized into allylmethyl sulfoxide (AMSO) and then allylmethyl sulfone (AMSO2)[29]
  • S-methylcysteine sulfoxide (Methiin)[28]
  • Dimethyl sulfides as well as allyl methyl sulfides, also present in garlic oil and similar to the diallyl sulfides are derivatives of allicin[22]
  • Thiacremonone (2,4-dihydroxy-2,5-dimethylthiophene-3-one), a cyclic sulfur bearing compound[31]
  • Garlicnins A1, B1-4, C1-3, and D1 (Cyclic sulfoxides);[32][33][34] thought to be formed sponaneously from allicin
  • Allixin, a cyclic non-sulfur component that accumulates in the necrotic areas of garlic bulb[35][36] that may reach up to 1% of the bulb's dry weight after a year[35]
  • Sodium 2-propenyl thiosulfate[37]

Finally, the protein fragment of garlic itself contains some bioactives. There is also a 14kDa glycoprotein known to be involved in the induction of natural killer (NK) cells[38] and thought to be involved in altering T-cell cytokine production, since the extract of garlic where the glycoprotein is found alters T-cells.[39]

In regards to the sulfur containing compounds, there are two main classes of traditional bioactives, which are pretty much either made from allicin spontaneously reconfiguring itself (this makes diallyl sulfide molecules, Ajoene, and vinyldithiins) or from the Glutamyl-S-allylcysteine being aged (this makes S-allylcysteine mostly). There is a protein fragment involved in immune health, and some cyclical bioactives with unknown origins

With some non-sulfur based bioactives including (note, some variants of garlic will be specified):

  • ACE inhibiting dipeptides (Ser-Tyr, Gly-Tyr, Phe-Tyr, Asn-Tyr, Ser-Phe, Gly-Phe, and Asn-Phe)[40]
  • β-Chlorogenin[26]
  • Nitrate at 183mg/kg (34–455mg/kg)[41]
  • The lignans Matairesinol (37.4µg/100g raw weight) and Secoisolariciresinol (26.6µg/100g raw weight)[42] thus able to produce endogenous enterodiol[43]
  • Quercetin at 47[44] to 80.6mg/kg[45] but usually not detectable[45][46][47]
  • Apigenin once reported to be 217mg/kg dry weight[48] but otherwise not detectable[46][47]
  • Myricetin once reported to be at 693mg/kg[44] but otherwise not detectable[47]
  • Kaempferol once reported at 1mg/kg[44] and usually not detectable[46][45][47]
  • Molybdenum at 2.80µg/100g[49]
  • Luteolin at 1.4% of a methanolic extract of the peels[50] but otherwise at low to undetectable levels in the bulb[44]
  • L-Methionine[26]
  • L-cysteine and related amino acids L-methylcysteine and L-ethylcysteine[26]
  • L-Arginine and related structures such as fructosyl-arginine[26]
  • Glutathione itself (93.5mg/100g[51])
  • Selenium containing molecules including selenate, Dimethylselenide, selenomethionine, selenocysteine, S-methyl selenocysteine and γ-glutamyl-S-methylselenocysteine;[52] structurally, the selenium replaces the sulfur of some garlic bioactives and of sulfur containing amino acids
  • Vitamin C (5.3mg/100g[51])
  • Caffeic acid (2.9mg/kg dry mass[47]) and ferulic acid (2.6mg/kg dry mass[47])
  • A dietary mannose-containing lectin[53] that acts on the insulin receptor[54] and does not agglutinate red blood cells[55] at 30.3ng/g fresh weight[54]
  • Furostanol saponins Voghieroside (A at 5.7mg/kg, B at 9.1mg/kg, C at 10.6mg/kg, D at 0.4mg/kg, and E at 0.3mg/kg; all isomer pairs) from the variant Voghiera[6]
  • Agigenin (not to be confused with Apigenin) 3-O-trisaccharide from the variant Voghiera[6]
  • Gitogenin 3-O-tetrasaccharide from the variant Voghiera[6]
  • Eugenol diglucoside (0.7mg/kg) and rutinoside (6.1mg/kg) in the variant Voghiera[6]

The bioactives in garlic that are not the unique sulfur containing ones are not present in very high levels, and it is likely that the things in this list are ingested at much too low of a dose to be bioactive

When looking at overall groups of molecules, an average garlic bulb is about 0.9% γ-glutamylcysteines and up to 1.8% alliin.[8]

Total flavonoids have ranged from 6.36-9.00mg gallic acid equivalents (GAE) per kilogram dry mass[56] and elsewhere 6.99–8.70mg,[48] 19.4mg/kg,[44] and 0.075–0.12mg/kg.[46] Garlic skin (the coating of the buds) has a poor content of sulfur containing bioactives.[57]

One major molecule is Alliin, which is rapidly converted to Allicin (probably not bioactive in the body) and then allicin is further degraded into either Ajoene (which is one major bioactive) or the the vinyldithiin and dithiin molecules (also bioactive), although S-allylcysteine also may play a role

When analyzing commerical garlic products, the allicin content appears to be less than 1ppm (less than 1µg per gram).[15]

1.3

Physicochemical Properties

Crushing or cutting a garlic clove to expose it to air (chewing also qualifies for damage, but there is less air exposure) the enzyme known as alliinase is activated and rapidly lyses the cysteine sulfoxides (alliin) to form the alkyl alkane-thiosulfinates of which allicin temporarily forms 70-80% of them.[8] This rapid conversion of alliin to allicin causes the characteristic garlic odour when initially cut, but due to allicin itself being instable it is then further degraded into ajoene and dithiins.[29][8]

Despite being the most prominent bioactive in garlic, allicin is highly instable to both heat and oxidation[29] and is broken down into the more stable vinyldithiins[17] or ajoene.[29][58] Even under best case scenarios, allicin in solution can reach a half-life of up to 12 days in 20-50% ethanolic extracts.[29]

Allicin has poor stability in processed products or in liquid solution, suggesting that products containing allicin may contain the catabolites of allicin instead (due to decomposition)

When looking at S-allylcysteine, it has a melting point of 223.3–223.7°C and is seen as a white crystalline powder (with minor yellowing after prolonged storage);[59] as the name suggests, it is structurally related to L-cysteine and unlike allicin or its parent compound γ-glutamyl-S-allylcysteine, S-allylcysteine appears to be quite stable and can remain unaltered in garlic for up to two years.[19] If S-allylcysteine is in an alkaline medium, within six days there may be some detectable catabolites (allylmercaptan and allylsulfide) although these changes do not occur in acidic medium.[59]

Relative to other compounds in garlic, S-allylcysteine is pretty stable and is commonly seen as an end-point of garlic metabolites; it can still degrade further into some catabolites if placed in an alkaline solution

In general, the oil soluble sulfur components of garlic (arising from the oil fragment) are known to carry the aromatic properties of garlic,[8] which mainly consist of the main diallyls (sulfide, disulfide, and trisuldie) as well as methyl allyl disulfide (and trisulfide), 2-vinyl-1,3-dithiin, 3-vinyl-1,2-dithiin, and Ajoene.

1.4

Formulations and Variants

The most basic variant of garlic supplement is the basic garlic powder, which is simply dehydrating the bulb and crushing it into a powder; it contains some alliin although usually not allicin since whatever allicin was form spontaneously reconfigues into its derivatives.[28]

Due to the dehydration (and assuming a 65% water content of the garlic cloves), one gram of the basic garlic powder is equivalent to about 2,850mg of raw garlic.

Garlic powder (when 'aging' is not mentioned) is simply a concentrated form of garlic supplement that is pretty much bioequivalent to consuming raw garlic bulbs, assuming the dose is corrected (with one gram of powder being equivalent to 2,850mg of the raw bulb)

Aging garlic for 20 months (at low temperatures and dissolved in 15-20% ethanol) produces 'Aged Garlic Extract', which is usually sold in 10% ethanol.[19][60][14] The major brand name for aged garlic extract is 'Kyolic', and the process of aging has the benefit of making the garlic supplement odorless.[19]

The molecular differences in aged garlic extract involves the Glutamyl-S-allylcysteine molecules. During the aging process, the parent molecules (γ-Glutamyl-S-allylcysteine and γ-Glutamyl-S-1-propenylcysteine) passively degrade over time to increase levels of S-Allylmercaptocysteine (SAMC), S-allylcysteine (SAC), and S-1-Propenylcysteine.[19] Kyolic as a product tends to be standardized to SAC (since it is seen as the major bioactive), and during the aging process SAC can increase from 200µg/g of the dry extract to 7,200µg/g dry extract (associated with full depletion of the parent compounds)[19] although to be sold on the market as 'Aged Garlic Extract' you only need a minimum of 0.05% (500µg/g) S-allylcysteine. Kyolic was specifically mentioned due to being a product used in many studies (either in humans or in vitro) and while some are partly funded by the producer of the supplement (Wakunaga Pharmaceutical)[61] there some independent trials that also return positive results.[20][62]

The aging process does produce some other unique bioactives as well as the above. This includes the tetrahydro-β-carbolines[63][64] and Nα-(1-deoxy-D-fructos-1-yl)-L-arginine[65] as well as other fructans.[66] Some molecules in these categories show direct antioxidant properties[67] and total fructans may be up to 0.22% of total dry weight.[66] Due to these unique bioactives and the increased level of Glutamyl-S-Allylcysteine derivatives, aged garlic extract has more antioxidative potential than does standard (fresh) garlic extracts.

Aging garlic tends to encourage the degradation of Glutamyl-S-allylcysteine parent molecules to lose their glutamyl groups, and this increases the levels of its derivatives such as S-allylcysteine. This variant of garlic supplement is also odorless

Garlic oil is a product of garlic manufacturing (usually by steam distillation),[68][23] which is concentrated for the fat soluble sulfur containing molecules; this mostly refers to diallyl sulfides (end product of ex vivo allicin breakdown) and usualy excludes the glutamyl-S-allylcysteines seen in Aged garlic extract.

Garlic oil tends to contain polysulfides (many sulfur groups) mostly of the diallyl class, and a standard breakdown of bioactives in garlic oil is as follows:[22]

  • Diallyl disulfide (26%)
  • Diallyl trisulfide (19%)
  • Diallyl tetrasulfide (8%)
  • Allyl methyl disulfide (13%)
  • Allyl methyl trisulfide (15%)
  • Allyl methyl tetrasulfide (6%)
  • Dimethyl trisulfide (3%)
  • Pentasulfide (4%)
  • Hexasulfide (1%)

At times, you can have an oil-macerated garlic oil, which is the same as above but contains Vinyl-Dithiins and Ajoene or an ether-extracted garlic oil, which has a higher content of vinyl dithiins (5.7mg/g) and ajoene (0.4mg/g) relative to garlic, and may have a total allyl sulfide content of 1.4mg/g[22] The macerated garlic oil contains alliin but not allicin, whereas the garlic oil contains neither.[28]

Garlic oil is a processed form of garlic catering towards the sulfur donating molecules, particularly diallyl disulfide (DADS). Unlike aged garlic, garlic oil is highly aromatic

Boiling garlic bulbs is known to inactivate the alliinase enzyme which degrades alliin into allicin (which then spontaneously begins producing other bioactives) and due to this boiling garlic bulbs (or, technically speaking, any high level of heat without cutting the garlic bulb first) would cause supplementation of alliin without necessarily forming any of the bioactives made from alliin since alliin does not appear to be metabolized.[28]

Boiling garlic has been noted to prevent properties of garlic from occurring including vasorelaxation,[69] anticancer effects,[70] and the increase in nitric oxide and IFN-α.[71] Conversely, it has been noted to augment some properties such as memory enhancement (diabetics rats).[72] Boiling does not modify its antioxidant properties relative to raw garlic when measured in vivo[73] or when testing the ability to prevent LDL oxidation[74] and the alterations in triglycerides and cholesterol seen with raw garlic are not affected by boiling.[73]

The above 'heating' applies to 60s of microwave cooking and 45 minutes of baking in the oven,[70] but 30s of microwave cooking is fine.[75] Crushing the garlic and letting it stand for 10 minutes preserves the bioactivity of garlic.[75]

Boiling garlic, or any heat treatment at high levels without first destroying the structure of the clove, will prevent alliin form converting into its catabolites (diallyl sulfides, vinyl-dithiins, and Ajoene) and prevent their activity in the body. This will prevent the blood flow enhancement and anticancer properties specifically, although the cognitive protective, lipid lowering, and antioxidant effecs seem mostly unaffected

2.

Molecular Targets

2.1

H2S

Hydrogen Sulfide (H2S) is an small gaseous signalling molecule akin to nitric oxide, informally known as a gasotransmitter due to its state[76] and produced by one of three enzymes known as cystathionine γ-lyase, cystathionine β-synthase, or 3-mercatopyruvate sulfurtransferase.[77][78] It seems that garlic itself, when incubated in red blood cells, produces H2S from garlic bioactives[79] and that H2S can relax blood vessels.[80] H2S is mostly produced in the blood vessels from cystathionine γ-lyase[81] although it may also be produced nonenzymatically.[82][79]

The main mechanism of action for garlic, as it pertains to the blood pressure reducing and blood flow enhancing properties, is merely acting as a reservoir of sulfur, which can be used to make the signalling molecule known as hydrogen sulfide (H2S), which can either directly relax vessels (via ion channels) or indirectly accelerate nitric oxide signaling

There is also some crosstalk with the H2S signalling pathway and the nitric oxide pathway, since H2S can degrade the molecule known as S-nitrosoglutathione,[83] which serves as an intracellular (and to a degree, extracellular[84]) reservoir of nitric oxide that garlic is known to stimulate.[85] Due to this, the influence of garlic on blood pressure and blood flow is in part due to nitric oxide signalling per se (the vasorelaxing effect of opening potassium channels to be discussed in the ion channels section[81]) and in part an influence of the hydrogen sulfide system unto the nitric oxide system.

Hydrogen sulfide production may also underlie the interactions of garlic bioactives and both TRPV1[86] and TRPA1[87] as well as the interactions between garlic bioactives and AMPK activation.[88]

The production of the gasotransmitter hydrogen sulfide (H2S) seems to underlie pretty much all other mechanisms of action that are attributed to garlic supplementation, which supports the hypothesis that production of hydrogen sulfide is the main mechanism of action of garlic supplementation

2.2

Ion Channels

Garlic and its bioactives appear to open potassium channels in vitro, and when measuring membrane hyperpolarization and relaxation (maximal efficacy reaching 20% of baseline) it appears that a water extract has been noted to have an EC50 value of 1.15µg/mL and isolated bioactives having EC50 values of 6.2nM (allicin) and 9.9nM (ajoene).[89] Since garlic is known to spontaneously form H2S in vitro and H2S itself is a potent potassium channel opener,[81] it is thought that the potassium channel opening properties of garlic are secondary to H2S.

Garlic components appear to be quite potent potassium channel openers in endothelial cells, and this is thought to be due to the production of hydrogen sulfide from these components (with more contribution of sulfur causing more vasorelaxation)

2.3

TRPs

Diallyl sulfide activates TRPA1 (a receptor that responds to noxious cold) with an EC50 of 254μM and reaching maximal stimulation of 90.8%, which is lesser than diallyl disulfide (EC50 of 7.55μM and reaching maximal stimulation of 76.6%) as well as diallyl trisulfide which activates TRPA1 with an EC50 of 0.49μM (490nM) and reaches maximal stimulation of 83.6%;[21] the efficacy of diallyl trisulfide is greater than the bioactive of mustard oil (allyl isothiocyanate at an EC50 of 1.47μM)[21] and Allicin itself has a fairly potent EC50 value of 1.32-1.91μM while its precursor (alliin) is ineffective.[90] This increasing potency correlates with increasing sulfur groups, which suggests that the activation of TRPA1 from hydrogen sulfide[87] underlies the influence of garlic bioactives on this channel.

Garlic[91] and mustard oil[92] also activate TRPV1 and the diallyl sulfides, with EC50 values of 151μM (diallyl sulfide), 36.7μM (diallyl disulfide), and 43.7μM (diallyl trisulfide) all of which are a potency significantly lesser than the reference compound Capsaicin (EC50 of 1.47μM).[21] Allicin is slightly effective (EC50 of 51.22μM) and its precursor (alliin) is ineffective[90] and there is a possibility that this is also due to hydrogen sulfide, which is known to activate TRPV1 directly.[86]

Interestingly, raw garlic has been found to activate TRPA1 and TRPV1 while baking the garlic (400°F for an hour in an oven) has failed to have the same effect[90] and TRPM8 (a receptor that response to both innocuous cold sensation and menthol from peppermint[93][94]) has not been activated by either form of garlic.[90]

Components of garlic appear to stimulate both TRPA1 and TRPV1, and while the efficacy on TRPA1 seems quite potent it is less potent than capsaicin (hot pepper extract) on TRPV1 activation. The activation of these channels is probably secondary to hydrogen sulfide production

2.4

AMPK

Numerous components of garlic have been noted to activate AMPK including Ajoene (LKB1 and SIRT1 dependent signalling, confirmed

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