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.
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
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)
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
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.
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;
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;
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;
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;
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
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.
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)
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 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)
"Chemical Constituents and Pharmacological Activities of Garlic /Allium sativum L.": A Review. 2020":https://doi.org/10.3390/nu12030872
Allicin is a lipid-soluble sulfur compound, which can be easily damaged by cooking and has the ability to provoke intolerance, allergic reactions, and gastrointestinal disorders.