Allicin
Phytochemicals

Author: chiara baratelli
Date: 31/03/2009

Description

Garlic, like other plants, has a defense system composed of as many different components. In order to protect itself from insects, garlic produces allicin when it is injured.

Allicin is mother nature's insecticide. Allicin was discovered in 1944 by Cavallito who first noticed its potent antimicrobial activity.

Textist

Textist

Chemically, allicin is a 2-propene-1-sulfinothioc acid S-2-propenyl ester;


Allicin is not present in garlic unless tissue damage occurs, and is formed by the action of the enzyme alliinase on alliin.

Alliinase is a homodimeric glycoprotein that belongs to the fold-type I family of pyridoxal-5'-phosphate-dependent enzymes. There are 10 cysteine residues per alliinase monomer, eight of which form four disulfide bridges and two are free thiols. Cys368 and Cys376 form a S--S bridge located near the C-terminal and plays an important role in maintaining both the rigidity of the catalytic domain and the substrate-cofactor relative orientation.

Thiol-disulfide organization in alliin lyase (alliinase) from garlic

Textist

Alliinase is irreversibly deactivated at pH 3 or below; in addiction, intestinal fluids further diminish the amount of allicin that can be produced; as such, allicin is generally not produced in the body from the consumption of fresh or powdered garlic. The use of a water-based extract of allicin stabilises the allicin molecule; this may be due to the hydrogen bonding of water to the reactive oxygen atom in allicin; also, there may be water-soluble components in crushed garlic that destabilise the molecule.
(Antibacterial activity of a new, stable, aqueous extract of allicin against methicillin-resistant Staphylococcus aureus)

Molecular mechanism

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Numerous studies have demonstrated that a garlic extract and its sulfur-containing compounds (allicin S-allylcysteine, alliin, diallyldisulfide, diallytrisulfide, and ajoene) inhibited nuclear factor kappa B (NF-kB) activation induced by various receptor agonists including lipopolysaccharide (LPS).
Toll-like receptors (TLRs) play a key role in sensing diverse microbial products and inducing innate immune responses.
The dimerization of TLR4 is required for the activation of downstream signalling pathways, including NF-kB. Therefore, TLR4 dimerization may be one of the first lines of regulation in activating LPS-induced signaling pathways and in the induction of subsequent immune and inflammatory responses. The sulfur compounds have specific sulfur chemotypes such as thiols, disulfides, thiosulfinates, sulfoxides, and sulfones; these react with the thiol groups to reduce an oxidative stressor such as H2O2 to disrupt the integrity of DNA. Allicin, containing thiosulfinate chemotypes, can react with cysteine; because TLR4 has several cysteine residues in both cytoplasmic and extracellular domains, garlic extract may interact with these residues in TLR4, leading to the inhibition of TLR4 dimerization.
So, allicin inhibites the LPS-induced dimerization of TLR4, resulting in the inhibition of NF-kB activation and the expression of cyclooxygenase 2 and inducible nitric oxide synthase . It demonstrates that a garlic extract can directly inhibit the TLRs-mediated signaling pathway at the receptor level suggesting this inhibition to be one of the mechanisms for the anti-inflammatory activity of garlic.
Garlic (Allium sativum) Extract Inhibits Lipopolysaccharide-Induced Toll-Like Receptor 4 Dimerization

Potential health benefits

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Several animal studies published between 1995 and 2005 indicate that allicin may reduce atherosclerosis and fat deposition, normalize the lipoprotein balance, decrease blood pressure, have anti-bacterial, anti-thrombotic and anti-inflammatory activities, and function as an antioxidant to some extent.

ANTIMICROBIAL ACTIVITY

Allicin in its pure form was found to exhibit:

• antibacterial activity against a wide range of Gram-negative and Gram-positive bacteria, including multidrug-resistant enterotoxicogenic strains of Escherichia coli;

Textist

For example, allicin and allyl-methyl plus methyl-allyl thiosulfinate from acetonic garlic extracts have shown inhibition of the in vitro growth of Helicobacter pylori, the bacterium responsible for serious gastric diseases such as ulcers and even gastric cancer.
(Allyl-thiosulfinates, the bacteriostatic compounds of garlic against Helicobacter pylori)

• antifungal activity, particularly against Candida albicans;

Textist

A cationic antibacterial peptide, polymyxin B, was evaluated as an antifungal antibiotic against various fungi when used in combination with allicin. Allicin was not lethal but could amplify the fungicidal activity of PMB. Their combined actions cause a structural damage to the vacuole as judged by the disappearance of its swollen spherical architecture. The vacuole-targeting activity of PMB was similarly amplified with t-butyl hydroperoxide as a substitute for the action of allicin. These findings suggest that the allicin-mediated lipoperoxide production in fungal plasma membrane is the cause of the enhancement in the cellular uptake of PMB as well as its action against the vacuole.
(Amplification of vacuole-targeting fungicidal activity of antibacterial antibiotic polymyxin B by allicin, an allyl sulfur compound from garlic)

Additionally, about amphotericin B,

which is the gold standard of antifungal treatment for the most severe invasive mycoses, it was demonstrated that oxidative damage was involved in its fungicidal activity. In this study (Allicin enhances the oxidative damage effect of amphotericin B against Candida albicans), allicin was shown to enhance significantly the effect of AmB against Candida albicans, although allicin did not exert a fungicidal effect. Further study first demonstrated that allicin-mediated oxidative damage, such as phospholipid peroxidation in the plasma membrane, via influencing the defence of C. albicans against oxidative damage may be the cause of the synergistic interaction between allicin and AmB. So, a combination of AmB with allicin may prove to be a promising strategy for the therapy of disseminated candidiasis.

• antiparasitic activity, including some major human intestinal protozoan parasites such as Entamoeba histolytica, Plasmodium falciparum and Giardia lamblia;

Textist

About malaria, potential new drug targets include Plasmodium proteases that play critical roles in the parasite life cycle. The major surface protein of Plasmodium sporozoites, the circumsporozoite protein (CSP), is proteolytically processed by a parasite-derived cysteine protease, and this processing event is temporally associated with sporozoite invasion of host cells. E-64, a cysteine protease inhibitor, inhibits CSP processing and prevents invasion of host cells in vitro and in vivo. It was tested allicin, for its ability to inhibit malaria infection. At low concentrations, allicin was not toxic to either sporozoites or mammalian cells, but inhibited CSP processing and prevented sporozoite invasion of host cells in vitro. In vivo, mice injected with allicin had decreased Plasmodium infections compared to controls. When sporozoites were treated with allicin before injection into mice, malaria infection was completely prevented.
(Antimalarial activity of allicin, a biologically active compound from garlic cloves)

• antiviral activity;

Textist

Garlic has been shown to have antiviral activity, but the compounds responsible have not been identified. Using direct pre-infection incubation assays, it was determined the in vitro virucidal effects of allicin against selected viruses including, herpes simplex virus type 1, herpes simplex virus type 2, parainfluenza virus type 3 and human rhinovirus type 2 . Virucidal activity and cytotoxicity may have depended upon the viral envelope and cell membrane, respectively. However, activity against non-enveloped virus may have been due to inhibition of viral adsorption or penetration.
(In vitro virucidal effects of Allium sativum (garlic) extract and compounds)

ATHEROSCLEROSIS & LIPOPROTEIN

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Garlic antiatherosclerotic properties are mainly attributed to allicin; it was evaluated its effects on atherogenesis in experimental mouse models. Dietary supplement of allicin, reduced the atherosclerotic plaque area in mice. LDL treatment with allicin significantly inhibited both native LDL and oxidized LDL degradation by isolated mouse macrophages. So allicin may affect atherosclerosis not only by acting as an antioxidant, but also by other mechanisms, such as lipoprotein modification and inhibition of LDL uptake and degradation by macrophages.
A 1999 study (Allicin-induced decrease in formation of fatty streaks (atherosclerosis) in mice fed a cholesterol-rich diet) demonstrated that allicin exerts a beneficial effect on lipid profile in hyperlipidemic rabbits. The objective was to investigate the effects of allicin on formation of fatty streaks (atherosclerosis) and lipid profile in mice. It was observed no statistically significant differences between blood lipid profiles of groups. Microscopic evaluation of aortic sinus formation of fatty streaks (atherosclerosis), however, showed that values for mice in the allicin-treated group were significantly lower.

ANTINEOPLASTIC

Allicin and Ajoene, a garlic-derived compound produced from pure allicin which has the advantage of a greater chemical stability than allicin, inhibit the proliferation and induce apoptosis of several human non-leukaemia malignant cells including breast, bladder, colorectal, hepatic, prostate cancer, lymphoma and skin tumour cell lines. Recently, topic application of ajoene has produced significant clinical response in patients with skin basal cell carcinoma. They were shown to inhibit proliferation and induce apoptosis of several human leukaemia cells. More significantly, ajoene profoundly enhanced the apoptotic effect of the two chemotherapeutic drugs: cytarabine and fludarabine in myeloid leukaemia cells through enhancing their bcl-2 inhibitory and caspase-3 activation activities.
(Ajoene (natural garlic compound): a new anti-leukaemia agent for AML therapy)

ANTIOXIDANT

Oxidative modification of DNA, proteins and lipids by reactive oxygen species (ROS) plays a role in aging and disease, including cardiovascular, neurodegenerative and inflammatory diseases and cancer. Extracts of fresh garlic, like allicin, exert antioxidant action by scavenging ROS, enhancing the cellular antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidise, and increasing glutathione in the cells. It inhibits lipid peroxidation, reducing ischemic/reperfusion damage and inhibiting oxidative modification of LDL, thus protecting endothelial cells from the injury by the oxidized molecules, which contributes to atherosclerosis. Allicin and the others organosulfur compounds inhibit the activation of the oxidant-induced transcription factor, nuclear factor NF-kappa B; protect DNA against free radical-mediated damage and mutations; inhibit multistep carcinogenesis and defend against ionizing radiation and UV-induced damage. It has also been shown to protect against the cardiotoxic effects of doxorubicin, an antineoplastic agent used in cancer therapy and against liver toxicity caused by carbon tetrachloride (an industrial chemical) and acetaminophen, an analgesic.
(Antioxidant health effects of aged garlic extract)

SIDE EFFECTS:

Textist

Side effects of allicin generally are mild and uncommon. Garlic appears to have no effect on drug metabolism, but patients taking anticoagulants should be cautious. It seems prudent to stop taking high dosages of garlic seven to ten days before surgery because garlic can prolong bleeding time.
(Health effects of garlic)

MeSH
Comments
2013-01-07T14:04:24 - Umberto Maccio

OTHER EFFECTS OF GARLIC AND HYDROGEN SULPHIDE

Introduction

In in vitro studies, garlic has been found to have antibacterial, antiviral, and antifungal activity. However, these actions are less clear in vivo. Garlic is also claimed to help prevent heart disease (including atherosclerosis, high cholesterol, and high blood pressure) and cancer.

Cardiovascular Effects

The known vasodilative effect of garlic is possibly caused by catabolism of garlic-derived polysulfides to hydrogen sulfide in red blood cells (RBCs), a reaction that is dependent on reduced thiols in or on the RBC membrane. In fact, from garlic is obtained an organosulfur compound, allicin, which is not present in garlic, unless tissue damage occurs, and is formed by the enzyme allinase on alliin. From allicin derives hydrogen sulphide, which is also produced in small amounts by some cells of the mammalian body and has a number of biological signaling functions.

Allicin synthesis

Role of H2S
In humans, the gas is produced from cysteine by the enzymes cystathionine beta-synthase and cystathionine gamma-lyase. It acts as a relaxant of smooth muscle and as a vasodilator. Eventually the gas is converted to sulfite in the mitochondria by thiosulfate reductase, and the sulfite is further oxidized to thiosulfate and sulfate by sulfite oxidase. The sulfates are excreted in the urine.
Due to its effects similar to nitric oxide (NO) (without its potential to form peroxides by interacting with superoxide), hydrogen sulfide is now recognized as potentially protecting against cardiovascular disease.
Thus, the cardioprotective role effect of garlic is caused by catabolism of the polysulfide group in allicin to H2S, a reaction that could depend on reduction mediated by glutathione.
Though both nitric oxide (NO) and hydrogen sulfide have been shown to relax blood vessels, their mechanisms of action are different: while NO activates the enzyme guanylyl cyclase, H2S activates ATP-sensitive potassium channels in smooth muscle cells, and induces hyperpolarization, how Goldman equation shows.

Researchers are not clear how the vessel-relaxing responsibilities are shared between nitric oxide and hydrogen sulfide. However there exists some evidence to suggest that nitric oxide does most of the vessel-relaxing work in large vessels and hydrogen sulfide is responsible for similar action in smaller blood vessels.

Vasorelaxation by hydrogen sulphide involves activation of K(v)7 potassium channels,2013

Role of S-nitrosothiols

Structure of Nitrosothiols Recent findings suggest strong cellular crosstalk of NO and H2S, demonstrating that the vasodilatatory effects of these two gases are mutually dependent. Additionally, H2S reacts with intracellular S-nitrosothiols to form the smallest S-nitrosothiol, thionitrous acid (HSNO), and a role of hydrogen sulfide in controlling the intracellular S-nitrosothiol pool has been suggested. S-Nitrosothiols have received much attention in biochemistry because they serve as donors of the nitrosonium ion NO+, and nitric oxide and some organic nitroso derivatives serve as signaling molecules in living systems, especially related to vasodilation. Red blood cells, for instance, release S-nitrosothiols into the bloodstream under low-oxygen conditions, causing the blood vessels to dilate.
The addition of a nitroso group to a sulfur atom of an amino acid residue of some protein is known as S-nitrosation or S-nitrosylation. This is a reversible process and a major form of posttranslational modification of proteins.
S-Nitrosated proteins (SNOs) serve to transmit nitric oxide (NO) bioactivity and to regulate protein function through mechanisms analogous to phosphorylation: NO donors target specific amino acids motifs; post-translational modification leads to changes in protein activity, protein interactions, or subcellular location of target proteins; all major classes of proteins can undergo S-nitrosylation; and enzymes play a primary role in regulation of S-nitrosylation.
Chemical characterization of the smallest S-nitrosothiol, HSNO; cellular cross-talk of H2S and S-nitrosothiols ,2012

Erection of penis
Like nitric oxide, hydrogen sulfide is involved in the relaxation of smooth muscle, because of K-ATP channels activated, like upon explained, that causes erection of the penis, presenting possible new therapy opportunities for erectile dysfunction.
Hydrogen sulfide and penile erection,2012)

Cholesterol

Moreover, allcin and ajoene, another chemical compund found in garlic, how in vitro studies show, inhibit HMG-CoA reductase, which converts HMG-CoA in mevalonate, and is involved in cholesterol synthesis, and this could partially explain the reduction of blood cholesterol levels.
HMG-CoA reductase HMG-CoA Reductase

Inhibition of cholesterol biosynthesis by allicin and ajoene in rat hepatocytes and HepG2 cells, 1994

Adverse effects
Garlic is known for causing halitosis, as well as causing sweat to have a pungent 'garlicky' smell, which is caused by allyl methyl sulfide (AMS). AMS is a volatile liquid which is absorbed into the blood during the metabolism of garlic-derived sulfur compounds; from the blood it travels to the lungs (and from there to the mouth, causing bad breath; see garlic breath) and skin, where it is exuded through skin pores.
Allyl Methyl Sulphide Allyl-Methyl-Sulphide

2012-02-13T22:50:32 - Matteo Marro

Role of garlic and hydrogen sulfide in hypertension

GARLIC is an important component in the complementary and alternative medicine. Experimental and clinical studies confirm that the ancient experience with beneficial effects of garlic holds validity even in prevention of cardiovascular disorders and other metabolic ills. Most recent data published after year 2000 convincingly point out that garlic and its various forms reduce cardiovascular risk, including abnormal plasma lipids, oxidized low density lipoproteins (LDL), abnormal platelet aggregation and a high blood pressure. (”Hypotensive effects of hydrogen sulfide via attenuating vascular inflammation in spontaneously hypertensive rats. 2008”)

Garlic constituents include enzymes (for example, alliinase) and sulfur-containing compounds, including alliin, and compounds produced enzymatically from alliin (for example, allicin). Allicin, that features the thiosulfinate functional group, R-S(O)-S-R compound, is not present in garlic unless tissue damage occurs and is formed by the action of the enzyme alliinase on alliin.

Cardioprotective effects of dietary garlic are mediated in large part by the generation of hydrogen sulfide (H2S). H2S has been best known for decades as a pungent toxic gas in contaminated environmental atmosphere, but it has now been recognized as a novel gasotransmitter in the central nervous and cardiovascular systems, similarly to nitric oxide (NO) and carbon monoxide (CO). Garlic-derived organic polysulfides are converted by erythrocytes into hydrogen sulfide which relaxes vascular smooth muscle, induces vasodilation of blood vessels, and significantly reduces blood pressure. Although its role in blood pressure regulation and interaction with NO is controversial, H2S, through its anti-apoptotic, anti-inflammatory and antioxidant effects, has demonstrated significant cardioprotection. As a result, a number of sulfide-donor drugs, including garlic-derived polysulfides, are currently being designed and investigated for the treatment of cardiovascular conditions, specifically myocardial ischaemic disease. (“Hydrogen sulfide-mediated cardioprotection: mechanisms and therapeutic potential. 2011”)

H2S can also be produced endogenously from L-cysteine by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE); the expression of these enzymes has been detected in various tissues. Recent study demonstrated that CSE was expressed in rat aorta, tail artery, mesenteric artery, and pulmonary artery whereas the expression of CBS was not detectable. (“The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. 2001”).

The importance of CSE was recently demonstrated in a mouse lacking CSE which showed reduced H2S levels and developed hypertension and reduced endothelium-mediated vasorelaxation. And also the use in rats of D,L-propargylglycine (PPG) (a CSE inhibitor) elevates blood pressure;daily intraperitoneal injections of PPG for 2–3 wk elevates systolic blood pressure: because this PPG treatment suppresses H2S production in vascular and other tissues, PPG-induced hypertension may result from reduced endogenous H2S production in vascular tissues; these data establish H2S as a new and important biologic signal molecule and as a new regulator of vascular blood flow and blood pressure ( “Hydrogen sulfide as an oxygen sensor/transducer in vertebrate hypoxic vasoconstriction and hypoxic vasodilation. 2006”) .

How H2S can contrasts hypertension? There are some theories:

  • H2S relaxes blood vessels and lowers blood pressure by opening ATP-sensitive K+channels in vascular smooth muscle (Gaso-transmitter hydrogen sulphide: potential new target in pharmacotherapy. 2010”) :the opening of these channels leads to membrane hyperpolarization, which in turn may close voltage-gated calcium channels. Alternatively, H2S may directly inhibit voltage-gated calcium channels in vascular smooth muscle cells.
  • It modulates the renin-angiotensin system , a hormone system that regulates blood pressure and water (fluid) balance. (“Hydrogen sulfide inhibits plasma renin activity. 2010”).When blood volume is low, juxtaglomerular cells in the kidneys secrete renin directly into circulation. Plasma renin then carries out the conversion of angiotensinogen released by the liver to angiotensin I. Angiotensin I is subsequently converted to angiotensin II by the enzyme angiotensin converting enzyme (ACE) found in the lungs. Angiotensin II is a potent vaso-active peptide that causes blood vessels to constrict, resulting in increased blood pressure. Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the tubules of the kidneys to increase the reabsorption of sodium and water into the blood. This increases the volume of fluid in the body, which also increases blood pressure. The release of renin is a process regulated by intracellular cAMP. Hydrogen sulfide down regulates cAMP production in some cell types by inhibiting adenylyl cyclase, suggesting the possibility that it may modulate renin release. It may also inhibits the up regulation of renin mRNA
  • Different studies demonstrates a correlation between H2S and other two gasotransmitters that have vasorelaxative effects, NO (nitric oxide) and CO (carbon monoxide): eNOS and heme oxygenase-2 (HO-2), the biosynthetic enzymes for NO and CO, respectively, are activated by calcium-calmodulin. Thus, endothelial activation by substances such as acetylcholine or bradykinin elicits formation of inositol 1,4,5-trisphosphate, which releases intracellular calcium to stimulate formation of NO or CO. It has been found a similar mode of regulation for CSE.(H2S as a Physiologic Vasorelaxant: Hypertension in Mice with Deletion of Cystathionine γ-Lyase. 2008). Genetic deletion of this enzyme in mice markedly reduces H2S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. NO acts through the stimulation of the soluble guanylate cyclase, which is a heterodimeric enzyme with subsequent formation of cyclic GMP. Cyclic GMP activates protein kinase G, which causes phosphorylation of myosin light chain phosphatase, and therefore inactivation of myosin light-chain kinase, and leads ultimately to the dephosphorylation of the myosin light chain, causing smooth muscle relaxation. To determine whether the H2S-induced vasorelaxation was mediated by this pathway, we studied the vascular effect of H2S in the presence of soluble guanylyl cyclase (sGC) inhibitors ODQ . Interestingly the H2S-induced relaxation was potentiated by ODQ ( [1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one] ) and so this suggests that the H2S-induced vasorelaxation is not due to the activation of the cGMP pathway.

  • H2S at physiologically relevant concentrations induced apoptosis of human aorta smooth muscle cells (HASMCs) via the activation of mitogen-activated protein kinases (MAPK) and caspase-3: the MAPK family represents important signal transduction machinery and occupies a central position in cell growth, differentiation, and programmed cell death. Different MAPK are activated by different stimuli, target different downstream molecules, and therefore perform different functions; hydrogen sulfide promotes the activation of RAF-MEK-ERK pathway that leads to its downstream enzyme cascades, eventually activating caspase-3. (“Hydrogen sulfide-induced apoptosis of human aorta smooth muscle cells via the activation of mitogen-activated protein kinases and caspase-3. 2004”)

H2S also plays an important role in hypoxic pulmonary hypertension: Anecdotal observations suggest a beneficial effect of garlic in preventing high-altitude symptoms. To determine whether garlic influences pulmonary vasoconstriction, it has been assessed the effect of garlic onpulmonary pressures in rats subjected to alveolar hypoxia and on vasoconstriction in isolated pulmonary arterial rings. Garlic gavage (100 mg/kg body wt) for 5 days resulted in complete inhibition of acute hypoxic pulmonary vasoconstriction compared with the control group. No difference in mean arterial pressure or heart rate response to hypoxia was seen between the groups. Garlic solution resulted in a significant dose-dependent vasorelaxation in both endothelium-intact and mechanically endothelium-disrupted pulmonary arterial rings. (”Garlic elicits a nitric oxide-dependent relaxation and inhibits hypoxic pulmonary vasoconstriction in rats. 2000”)

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