Indian Journal of Experim cntal Biology Vol. 39. Apri l 200 1. pp. 310-322

Review Article

Role of garlic (Allium. sativum L.) in human and plant diseases

UP Singh ', B Prilhiviraj ', B K Sarma ', Mandavi Singh2 & A B Rai 'Departmen t of Mycology and Pl ant Pathology. Institutc of Agri cultural Scienccs. Banaras Hindu Universit y, Varan as i 221005, India Fax: 9 1-542-3 17074. E mail: ups @ banaras. crn et.in !Dcpart mcnt of Anatomy. In sti tute of Mcdical Scicnces, I3anaras Hindu Uni ve rsity, Va r3nasi 22 1005. India, JDepartment of Mcd icinal Chemistry, In stitutc of Medical Scienccs. Banaras Hindu Univcrsity, Varanasi 221005. India

A n:surgcncc of intcrest in garlic due to recent rcvelations of its bcneficial cffec ts in th c treatmcnt of various hum an and plan t diseascs and also due to validation of claims made in traditional systems of medici nc has resulted a plcth ora of publi ca ti ons on diffcrcnt a pects of garlic in reCC I1l years. Chcmical constituents of garlic and their variati ons on the mcth ods of isolation havc been discussed in the prcsent rev iew. Effect of garlic and it s constituents aga inst various human anel plant pathogenic and sap roph yt ic mi croorganisms has also been reviewcd.

Garlic (A lliulIl sativulII L.) is used worldwide as a view of the variety of bioactivities th at garlic and its l food additive, spi ce and medicine. In Ayurveda , it various preparations exhibit, it is considered has been described as a gastric sti mu lant. It aids appropriate to comp il e the various findings in a digesti on and is given in tlatulence. It has special systematic manner and an attempt in this direction has influence over the bronchi al and pulmonary secreti ons been made in this bri ef review. and in promotion of fl ow of menses. Garlic is used as ClJell/ica l constituents of garlic - Garli c is a rich a tonic, carminati ve and stimulant. In large doses, it is source of organosulphur compounds showing a an irritant and produces flatulence, headache, nau sea va ri ety of bi ological activi ti es. The chemical and even diarrhoea. As a local stimul ant and ilTitant, it constituents from garlic cl oves (b ul bs) vary with the causes red ness of th e skin and vesication. It is appli ed isolation procedure and obviously many of the to the nose of hysterical patients when in a state of compounds report ed from thi s source have been swooning. Gi ven wi th common salt , it rel ieves colic proved to be artifacts. Thus, while ga rlic oil obtained pain and nervous headache. It is used as a vermi fu ge by steam disti ll ation of garlic cloves was proved to be to ex pel round worms. It causes diuresis and hence essentially cl iall yl di sulphide (1) accompanied by 26 used in dropsy . In cold catarrh of chi ldren, brui sed lesser amounts of diallyl tri-and tetra-sulphides . garlic is applied to the chest as a poulti ce or lini ment. Ext rac ti on of garli c with eth yl alcohol at room It is also used as a remedy to bites of venomous temperature yield s ox ide of diallyl disulphide (2) reptil es. The rubificent action of garlic is enh anced by call ed all ici n27. Extraction of garlic with ethanol at addition of mu stard powder. It is rubbed over subzero temperature yields28 an adourl ess am ino acid, ringworm for reli ef. Garli c juice boiled wi th salad oil (+)-S-allyl-L-cystein e sul foxide (3) whi ch is named gives reli ef from earache. It is beneficial in several alli in (Fi g. I). Odourl ess alliin has been proved to be forms of atonic dy spepsia and is effecti ve in the th e precursor of alli ci n, the main odorous principl e of treatment of tuberculosis. garlic and conversion of the forme r to latter takes Many of these effects have been substantiated by place under th e influence of an enzy me, allinase modern research and garli c has been proved to eli cit whi ch comes in contact wi th alli in on ly when garlic 2 5 6 antimicrobiaI . , antihypertensive , hypol ipidemic 7-'J, bul bs arc CLl t or crushed. It is for this reason that the Il epatoprotectlve. 10 , anti'd 'la be tl. c 11 -15 ,and' In secliclc.. I a 116 bul bs are odourless unless cut or bruised. properties. Immunomod ulati on and antitumor All in

,..--"'-U<.W.!...... ""-!.!..n .. CH2 = CH - CH2 -S - S - CH2 - CH = CH2 1

Allium sativum_!---"E1"-'=

Fig. I-Variation in chemical constituents of garlic due to change in isolat ion procedure CH2 = CH - CH2 - S - Cl-i2 - CH - COOH ~ I 3 0 NH2

CH2=CH-CH2-S-0H /k:'NH3 CH3-CO-COOH 4

-H20 2 x CH2 = CH - CH2 - S - OH • CH2 = CH - CH2 - S - S - CH2 - CH = CH2 J. 4 2 0 Scheme I ammonia and pyruvic acid . Two molecules of o f /N~ sulphenic acid then react together to give alli ci n by ~C /S~ C0 2 H loss of a molecule of water (Scheme I). Subsequent research has revealed that cysteine 6 sulfoxide fraction of garlic consists of 85% alliin (3) o along with 2% S-propylcysteine sulfoxide (5) and f H 3 C / S ,S/ C~ 13% S-methyl cysteine su lfox ide (6). Action of allinase on this mixture affords, besides alli cin, 8 allylmethanethi osulfinate (7), methyl methanethio­ sulfinate (8) and other mixed or symmetrical thi osu lfinates of th e general structure, R-S(O)-S-R' where Rand R' represent anyone of methyl, propyl or all yl groups. Obviously all these thiosul finates are 3t found to be present in garl ic extract . Lawson & 9 coworkers.l2 have shown that in addition to endogenous allii n (3), a reserve for alli in ex ists in the C6H IOS20 ~ C(, HgS2 + H20 precursor compound, y-glutamyl-S-allyl cystei ne (9) Mechanistically speaking, allicin first breaks down and is present in a significant quantity in freshly­ into 2-propene sulfenic ac id (4) and thioacrolein (12). picked garl ic cloves. While two molecul es of sulfenic acid regenerate a Analysis of garli c extracts)) using GC-MS revealed molecule of allicin by loss of a molecule of water, two the presence of mixture (2.4 : I) of two compounds molecul es of thi oacrolein undergo Di els-Alder (79%) which have been proved to be 3-vi nyl-[4H]- cyclisation to give cyclic 1,2 dithiins (Scheme II ). 1,2-dithiin (10) and 3-vinyl-[6H]- I,2-dithiin (11) Thioacroleins may also cycl ise in a different (Scheme II ), on the bas is of comprehensive spectral manner to give 2-vinyl-[4H]-I,3-dithiin (13; Scheme analysis. Compounds (10) and (11) are regarded as II ) which is al so found to be present in the fracti on. dehydration products of all icin (2) and th eir formation Other volati le components of garli c ex tract detected is considered to take place during gas chromatography by GC-MS analysi s have been proved to be allyl according to the equati on: alcohol (5.4%), methyl all yl disulphide (1.2%), diallyl 312 INDIAN J EXP. BIOL., APRIL 2001

disulphide (5.7%), dimethyl trisulphide (2.4%), allyl aqueous acetone for 4 hr gives a mixture containing methyl trisulphide (1.5 %), diallyl trisulphide (1.0%) ajoenes. Removal of nonpolar fraction by washing of JJ and sulfur dioxide . Volatiles identified in garlic oils this mixture with pentane and subsequent extraction are suprisingly few and it has been considered that with CHzClz yields mixture (4:1) of Z-ajoene (18a) investigation of volatiles using modern techniques and E-ajoene (18b). The synthetic material is such as HPLC or capillary GC-MS would indistinguishable from ajoene obtained from garlic. considerably extend the list of components. In fact, a When an ether-soluble fraction of methanolic temperature-programmed GC-MS analysis of garlic extract of garlic is stored in aqueous methanol for 4 essential oil has revealed a group of previously days at 25°C and then successively extracted with unknown cyclic and acyclic organo-sulphur hexane and methylene chloride, ajoene has been compounds of which the compounds 14 - 17 are found to be present in the latter fraction. Hexane­ particularly important because of their Jipo-oxyginase soluble fraction contains several divalent sulfur inhibitory activity. Interestingly, most of these compounds and these are identified as diallyl compounds are generated upon heating pure samples J4 disulphide (1), diallyl trisulphide, diallyl of diallyl disulphide • letrasulphide, allicin (2), and cyclic dithiin (10) and 2- Allicin (2) undergoes self-decomposition even at vinyl-[4H]- 1,3-dithiin (13). A compound isolated room temperature and decomposition products may from oil-macerated garlic by silica gel column condense spontaneously to give a variety of chromatography and preparative TLC, has been compounds. One of these compounds of importance is identified as Z-4,5,9-trithiadeca 1,6-diene-9-oxide ajoene (both E and Z varieties) which is well known (19) from NMR and MS analyse 5. for its anti thrombotic properties. Taking a cue from the self-condensation of methyl methane thiosulFinate 10 2,3,5-trithiahexane 5-oxide, the structure of ajoene Essential oi l of garlic, an item of commercial is settled as 4,5,9-trithiadodeca-1 ,6, II-triene-9-oxide importance, is obtain ed mainly by steam distillation (18) and it is prepared by heating allicin (2) with a of garlic and this product differs from garlic extract mixture of water and acetone. Three molecules of prepared at room temperature. In place of allicin (2), allicin give two molecules of ajoene (E and Z) and ajoenes (18) and a variety of dialkyl thiosulphinates, one molecule of water. The mechanism of formation known to be present in garlic extract, the essential oil of ajoenes from (2) has also been postuiatedZ6 of garlic has been reported to contain a mixture of (Scheme 1IJ). diallyl and allyl methyl sulphides, disulphides and J5 Ajoene may also be prepared synthetically from trisulphides and other minor components . diallyl disulfide. Peracetic acid oxidation of diallyl In addition to organosulphur compounds, peptides, disulfide (1) gives allicin (2) which on refluxing with steroidal saponins, f1avones and other phytochemicals

12

12 10 11

s~ - CI s 12 13 Scheme II SINGH et al.: ROLE OF GARLIC IN HUMAN & PLANT DISEASES 313

15

~S'S~S""S~

16 17

Z - ajoene ( cis fonn) E - ajoene ( trans fonn) a 18 b

19

HO

20

Glc

0 11 2 21 : Rl=H. R =Gal-(1-44) p-Glc-(1-43)-p-Glc-(1-43)-p-Glc-(1-42)-Glc

22: R1=OH. R2 = p-GaH1-44)-p-Glc Scheme III 314 INDIAN J EXP. BIOL., APRIL 200 1

6 as by synthesis . In addition, several other tri- and di ­ 36 peptides have also been isolated . T he presence of fl avonol, querceti n (20) has also been detected in 37 garli c . Reports of isolati on of bioactive steroidal saponins from garlic are there but the structures of all of these saponins could not be retri eved from the 20 60 rather obscure journals .38.39. Two of the saponins Cii > 38 . ~ repon ed earli er , have been identified as (21) and

~ C/) (22). ;f!. 40 Effect of garlic 0 11 fU l/ gi - Antifungal ac ti vity of garlic started with the testing of garlic bulb extract against some fungi. Appleton and Tanse/I fi rst used garli c extract against some zoopathogenic fungi with signifi cant growth inhibition. Later, Barone and Tanselo have reported the isolati on, purification, identification, synthesis and kineti cs of acti vity of the o 50 100 150 200 250 300 inhibitory principle of A. sativlfJ l1 on some Cal/ dida Concentration (~g ml") species and postul ated a hypoth esis for its mode of Fig. 2-Effect of ajocne on the survival of second stage juveniles action. Effect of aqueous garlic extract on fun gi of Heferodem cajalli. causing mycotic diseases in human beings has also 22 have also been isolated fro m garlic. Seven dipeptides been investigated . In a preliminary experiment, isolated from the concentrated aqueous extract of fungicidal effect of garlic leaf extract has been 24 garli c have been identified as Ser-Tyr, Gly-Tyr, Phe­ reported by Mi shra and Dixit . Effect of aqueous Tyr, Asn-Tyr, Ser-Phe, Gly-Phe and Asn-Phe from extract of garlic leaf on chickpea s.eeds and wilt and sequence anal ys is, FAB mass spectral analy sis as well stem rot of chickpea caused by Fusarium oxysporlll11

THIRD DAY SIXTH DAY

c:=J Tota l hatche­ 420 ~ Dead

360

300

"- i! 24 E 1 :J Z 180

120

60

W W+G 50 100 200 300 W W+G 50 100 200 300 ( onc(!ntration (pg IT1C1~

Fi g. 3-Effect of ajoene on th e egg hatchi ng of Heferode m caj alli. SLNGH el al.: ROLE OF GARLIC LN HUMAN & PLANT DISEASES 315 f. Sp. ciceri and Sclerotinia sclerotiorum has been damage of cell wall of ajoene-treated hyphae and seen. It has been observed that germination of treated conidia of A. niger and it has been postulated that like chickpea seeds is delayed and seedlings arising from other antifungal agents, ajoene also acts on the cell 25 2 them do not show wilt symptoms • Possible use of wall of fungi • garlic leaf extract in controlling plant diseases under Effect of ajoene on spore germination of some field conditions has been suggested. plant pathogenic fungi, viz .. Alternaria solani. A. tenuissima, A. tntlcma. ALternaria species, Chicken infected with Candida albicans have been Colletotrichum species, Curvularia species, Fusarium 41 lini. F. oxysporum. F. semitectum and F. udum has successfully treated by garlic • Antifungal activity of 3 garlic has also been reported against seven species of been noticed in vitro by Singh et al. and it has been Candida and two species of Cryptococcus present in observed that at 100 JlglmL concentration, spore 42 human serum • Intravenous administration of garlic germination of some fungi is completely inhibited. While working on the effect of ajoene on extract inhibits the growth of Cryptococcus 44 43 Plzytophthora drechsleri f.sp. cajani, Singh et al. neojormans present in plasma and cerebral fluid . Effects of ajoene and other fractions of garlic have noticed differential response of this chemical on against Aspergillus niger and Candida aLbicalls have different developmental stages of the fungus. For been studied by Yoshida et al. 2. Out of six fractions, instance, while mycelial growth is completely ajoene has shown strongest activity against the growth inhibited at 25 Jlg/mL, maximum effect is observed of A. niger and C. albicans at a concentration of <20 on sporangium formation and its germination at a Jlg/mL. Ajoene which is hi ghly inhibitory to C. very low concentration (2.5 and 3.5 Jlg/mL). glabrata. C. tropicalis. Trichophyton mentagrophytes. Zoospore germination is affected at slightly higher Tricosporon beigelii and Saccharomyces cerevisiae concentration (20 Jlg/mL). Treated zoospores produce has been found to be superior to allicin. Scanning 2-4 germ tubes and is not dose-dependent. electron microscopic study has revealed severe Fromthing and Bulmer23 have also noticed inhibitory effect of aqueous extract of garlic on 20 / Cryptococcus neoJormans. Effect of garlic, its constituents and commercial garlie supplement products has also been studied45 on several fungi, viz .•

>-,6; Trichophyton mentagrophytes. T. rubrum. T. tonsurans. T. schoenleinii. Microsporum audouinii. 15 - M. canis. Aspergillus jumigatus, Candida albicans and C. stellatoidea and their efficacy is compared ...,(f) (f) with ketoconazole. Allicin is generally less effective >, u 0 than ketoconazole, but is superior to latter against :... Aspergillus Jumigatus and Candida spp. Ajoenes ...c:Cll .... 10 - (E&Z) are effective against C. stellato ides, but less 0 .... effective against C. albicalls. In general, the :v .0 antifungal effects of garlic compounds have been E acrolein or some similar unsaturated aldehydes. products on mites has not been reported earlier. Only Phytoncides, a chemically undefined group of recently acaricidal effect of ajoene has been studied 27 5o substances, have been reported to be antibacteriaI . . using spotted mite (TetrallYcllUs urricae Koch) and Allicin, isolated from garlic by steam distillation of complete mortality (100%) has been observed with crushed cloves has been found to be effective against 0.075% solution (w/v) after 14 hr of treatment which many gram-positive and gram-negative bacteria is comparable with conventionally used acaricides. At belonging to Staphylococcus, Streptococcus, BaciLLus lower concentration (0.05%), ajoene affects facundity and Vibri027. Mechanism of action of allicin has been and juvenile survival (the survival rate being 37.56% reported to be due to its ability to inhibit sulthydryl at this concentration without affecting the contall1l11g enzymes51 and RNA synthesis in male:female ratio). The results suggest that ajoene, bacteria52 . Effect of a bacteriostatic concentration of besides having direct acaricidal effect, can also check allicin (0.2 to 0.5 mM) on growth of SalmoneLLa resurgence of the pest. Use of ajoene for the control of 6 typhimurium shows a pattern characterised by (i) a lag T. urticae under field conditions is quite possiblel . of approximately 15 min between addition of allicin Effect of garlic 011 Ilematodes - Effect of ajoene and onset of inhibition; (ii) a transitory inhibition (IS) on survival of second stage juveniles of phase whose duration is proportional to allicin Heterodera cajani which causes root knot disease in concentration and inversely proportional to culture pigeonpea (Cajanus cajan (L.) Millsp.) has been density; (iii) a resumed growth phase which shows a tested in our laboratory and it has been noticed that lower rate of growth than in uninhibited controls; and survival percentage is reduced to zero at 300 Ilg/mL (iv) an entry into a stationary phase at a lower culture of ajoene (Figs. 2,3). density52. Kinetics of decline of populations of Salmonella Effect ,of garlic all blue-greell algae - In order to typhimurium and Escherichia coli in the presence of explore the possibility of use of garlic or its products freshly reconstituted dehydrated garlic powders has for control of plant pathogens in the field conditions, 53 been studied by Johnson and Vaughn . According to it is of paramount importance to know their effect on them, there is a significant bactericidal property of non-target organisms, particularly, blue-green algae. this powder on the above mentioned bacteria. Though With this objective in view, the effect of ajoene on the the use of garlic for the treatment of tuberculosis with growth of Nastac calcicola has been studied in our remarkable cure rate had been reported from Dublin university (unpublished work) and it has been Hospital and New York city around the turn of observed that at the concentration of 6-20 ppm, the twentieth century, the concentration of the garlic growth of alga decreases up to 4th day of incubation SINGH et al.: ROLE OF GARLIC IN HUMAN & PLANT DISEASES 317 and thereafter increases up to 14th day while lower further study. Diallyl disulphide (1) has been reported doses do not have any effect. to inhibit linear microsomal lipid peroxidation In another experiment, it has been observed that the induced by doxorubicin, a well known anticancer heterocyst formation is affected by ajoene. At I ppm, drug. As the oxidative injury caused by doxorubicin the number of heterocysts sli ghtly decreases as restricts its clinical use, the clinical efficacy of this compared to control but at 5 and 10 ppm the number drug can be improved, if used in combination with 56 increases significantly in compari son to control (Fig. diallyl disulphide • It is interesting to note that most 4). The use of ajoene against plant pathogens may, of the garlic oil components could be obtained simply therefore, indirectly help in nitrogen fixation. by pyrolysis of diallyl disulfide (1) and, therefore, Effect of garlic on rats - With the objective of their presence is regarded as a consequence of heat finding out whether ajoene, a constituent of garlic, has (during steam distillation) on allicin (2) and diallyl any effect on rats, it was injected intraperitonially to disulfide (1). Obviously , any culinary procedure that female and male wister rats (unpublished work). In exposes garli c or garlic spiced food to heat generates female rats it was injected before and after compounds with possible health benefits associated fertilization of the ovum at the rate of 10, 20 and 40 with anti oxidant or LO inhibitory activity. mg/kg body weight in single and multiple doses. In all Hypolipidel'nic. hypochoLesterolaemic. antithrom­ the experimental groups, the average number of live botic alld antidiabetic properties of garlic - Garlic fetuses was higher than those of corresponding preparations have been shown to lower the levels of contro ls and the weight of ovaries at full term was serum cholesterol and triglyceride through inhibition comparatively increased. In pregnant female rats, at of their biosynthesis in liver and of oxidation of low 7 9 full term, when the fetuses were removed, the weight density lipoproteins • • The garlic constituent, alli in of viscera, like liver, spleen and kidney, was found to (3) has hypolipidcmic8 activity and both alliin and S­ be nearly similar to those of controls, whereas in methyl cysteine sufloxide are endowed with I2 13 nonpregnant female rats, the weight of these viscera antidi abeti c actions . . A combination of garlic and was comparatively reduced. In male rats the weight of ginger has been claimed to be superior to garlic alone 4 li ver, spleen, kidney and testes was reduced in treated in reducing serum lipids as well as blood glucose' . A groups as compared to control male rats. recent study reveals garlic protein to be similar in Antioxidant activity of garlic - Garlic oil and some composition to soya protein and it exhibits 57 of its components have been reported to inhibit hypolipidemic action • Effects of aspirin and garlic lipooxygenase (LO), one of the enzymes involved in powder supplementation on some clotting parameters arachidonic acid metabolism which may be related to in rabbits show that garlic powder supplementation to 34 its biological properties . Of the different cholesterol rich diet is more advantageous than aspirin components of garlic oil that shows significant LO alone because it has the beneficial effects on both 58 inhibitory activity, 2-(2',3'-dithia-5'-hexenyl)-3,4- blood clotting and plasma cholesterol level . Some dihydro-2H-thiopyran (14), 3-(2',3'-dithia-5'-hexenyl)- steroidal saponins isolated from fresh garlic bulbs also 3,4-dihydro-2H-thiopyran (15), 6-methyl-4,5,8,9- exhibited inhibitory effect on blood coagulabilit/o. tetrathiadodeca-I , ll-diene (16) and 4,5,9,10- Beneficial effects of garlic and its preparation tetrathiatrideca- l, 12-diene (17) display lC50 values against atherosclerosis and coronary thrombosis are toward soybean l5-lipooxygenase enzyme within a considered to be due to their ability to lower serum range of 8-37 11M, in comparison to 90 IlM shown by cholesterol 19 and inhibit aggregation of blood 59 E- and Zajoenes (18). A structure - activity platelets . Administration of aged garlic extract over relationship study made by these authors using garlic an extended period significantly reduces epinephrine oil components and structurally related synthetic and collagen-induced platelet aggregation. While model compounds reveals that LO inhibitory activity early work reports allicin (2), allyl methyl trisulfide increases with molecular weight up to a certain point and diallyl trisultide to be the active constituents, 2- and that changes made in the molecules by addition or vi nyl-[4H]-1 ,3-dithiin (13) and ajoene (18) have been removal of unsaturation have only minor influence. proved to be the potent anti thrombotic agents. Unlike While LO inhibitory activity of garlic oil components several other inhibitors of platelet aggregation, these and homologues may be attributed primarily to compounds are found to inhibit aggregation induced 60 61 lipophilic interactions, the ability of these by all known inductors · • In an effort to understand organosulphur compounds to bind to LO iron merits the structure activity relationship. a comparative study 318 INDIAN J EXP. BIOL. , APRIL 200 1 of antithrombotic activity of (E and Z)-ajoene and of chloroquine against plasmodial parasite. The actual synthetic homologues has been made and it has been mechani sm of action is not yet known. found that among the components of garlic oil, Z­ Hepatoprotective activity and detoxification effects ajoene (18b) is most active. The central carbon­ of garlic - Garlic preparations and organosulphur carbon double bond and disulfide groups of ajoene compounds present in garlic have been proved to be have been proved to be essential fo r activity. On the responsible for protection of liver against basis of this study it has been postulated that platelet acetaminophen and bromobenzene tOXICity·.. 10 38 . membrane sulphydryl groups participate in a Acetaminophen-induced acute cataract and other disulphide exchange reaction with ajoene and the occular ti ssue damage in mice could be prevented by resultant alteration in the membrane prevents treatment with diallyl disulfide 0), preferably in aggregation. Apitz-Castro et at. 62 have established the combination with N-acetyl L-cystine. The pl ausible molecular basis of the anti platelet action of ajoene mechanism fo r this detoxification effect has been and it has been shown that it directly interacts with 68 Cl9 postulated • Khanum and co-workers have observed fibrinogen receptor. One of the remarkable features of that long term feeding of fresh garlic, or its oi l, ajoene is that its antiaggregatory effect is synergistic 63 reduces the toxic effects of azoxymeth ane, a with that of prostacyc1in, aspirin and indomethacin . carcinogen. Iron nitrilotriacetate-mediated Dipeptides isolated from concentrated aqueous nephrotoxicity is diminished by one week of oral extract of garlic show angiotensin I-converting pretreatment of male albino wister rats with garlic enzyme inhibitory activity. These are considered to be 70 oi l • Most of the toxins damage tissues by free radical responsible, at least in part, for antihypertensive 6 formation and garlic principles counter them by th eir activity of garlic in animals and humans . Efficacy of d etoxi·f yl£lg· actions. 71. garlic powder, extract or oil in treatment of patients Allticancer and il1ll1lullolllodulalory activity of with hyperlipidemia has, however, been 64 65 garlic - Several ingredients of our dietary system are questi oned . . Efficacy of garli c principles on known to have the potential against occurrence of hyperlipidemic patients may, however, differ cancer in human beings. A variety f phytochemicals according to etiology of the disease and thi s aspect present in edible fruits and vegetables has been needs further investigation. proved to inhibit carcinogenesis by appropriate Effect of garlic on AIDS (HIV) viruses all~ 6 experimental studies but evaluation of anticancer malarial parasites - Apitz-Castro and coworkers - acti vity of garlic, its extract and of its constituents has have observed that ajoene inhibits pl atelet aggregati on been done recently despite the reference of garli c as by allosterically inactivati ng the platelet integrin GP an effecti ve remedy fo r tumors in Codex Ebers, an lIb/III, and this prompted Tatarintaev et al. 66 to Egyptian Medical Papyrus dating back to around 1550 propose that ajoene may also inhibit both adhesive BC (Ref. 33,72). Kyo et al. 17 have studied the interacti ons and fu sion of leucocytes and may antitumor activities of aged garlic extract and antagonize integrin-dependent processes in HIY­ observed that it stimulates the proliferation of mouse infected T-Iymphoblasts. Study has shown that ajoene spl een cells and the release of cywkines, increases (18) inhibits platelet aggregation, HIY -medi ated K activiti es and enhances phagocytosis of peritoneal syncytia formation, replication of HIY-I (RF) in H9 macrophages. It also stimulates the reactivity of cell s and replication of HIY-I (LA Y-BRU). Based on lymphocytes in response to cytokines and mitogens. their results it has been suggested that administrati on Aoed oarlic extract (a rich source of ajoene) of ajoene in combination with conventional anti-HIY I:> I:> signi ficantly inhibits the growth of sarcoma- 180 drugs may be a promising approach for treatment of (all ogenic) and LLl2 lung carcinoma (syngenic) cells AIDS. transplanted into mi ce. Increased N K and ki ller Perez et af. 67 have investi gated anti Plasmodium activities of spleen cells have been observed in berghei activity of ajoene on experimental mice. They sarcoma-180 bearing mice treated with aged garlic observed inhibition of malarial parasite following extract. Aged garlic extract has thus been proved to be treatment with ajoene. However, when ajoene was a potent biological response modifier in NK cells and lI sed as a mixture with a noncllrative dose of T-Iymphocytes as it inhibits the growth of ch loroquine there was a complete prevention of the transplanted tumors. A protein fraction from aged development of parasitemia in mice. It is believed that garlic extract has also been reported to enhance ajoene synergistically enhances antimalari al activity SINGH et al.: ROLE OF GARLIC IN HUMAN & PLANT DISEASES 3 19 cytotoxicity and proliferation of human tumorogeni c lymphoid ce ll line deri ved from Burkitt lymphocytes73. lymphoma (BJA-B) and observed the cytotoxic acti on in the range 2-50 Ilg/mL depending on the cell Direct cytotoxic effect of garlic and its extract has density. Although the exact mechani sm o f cytotoxic been studied. Dietary (5 % in diet) and subcutaneous action of ajoene is not known, it is assumed th at it administration of garlic extract have been reported to reacts with cellular SH functi ons to exhibit its inhibit the growth of Morris hepatoma 3924A in 74 cytotoxic activity. Z-ajoene (18a) has also been rats . Inhibition of growth of murine transitional cell shown to induce cell death by apoptosis in hu man carcinoma (MBT-2) in mi ce by intraperitoneal 75 HL-60 pro myelocytic leukemi a cell s, MGc-803 injecti on of garlic extract has been reported . 76 gastric mucoid adenocarcinoma cell s and Molt-4T Belman has shown inhibition of 7, 12- 86 lymphocyte leukemi a cell s . dimeth ylbenzanthracene-induced phorbol-myristate­ There are several firms now in India and abroad acetate pro moted skin papillomas in mice by topical which prepare garlic capsul es that are recommended application of garlic oil. fo r the diseases of lungs, atherosclerosis, hi gh blood Diall yl sulphide and diallyl disulphide have been pressure, gout, rheumati sm, asthma, chronic bronchial used to determine inhibition of ary l amine N­ catarrh, intestinal complaints and loss of appeti te. acetyltransferase (NAT) activity in a human colon These capsules are also claimed to renew the blood, tumor (adenocarcin oma) ce ll line and it has been clean it of all impurities, regul ate digesti on, remove observed th at NAT acti vity is inhi bited by these all parasites from the intestines and cure bacterial organosul phur compounds in a dose-dependent in fection. Garlic fri ed in mustard or coconut oil is an 77 manner • Modulation of hepatic drug-metabo li zi ng excell ent anti septic suitable fo r applicati on in scabi es enzy mes in rats treated with dialkyl sulphides and and wounds. Its juice mi xed with salt is applied to di sulphides has been studied. The results suggest a bruises and is cl aimed to re li eve neuralgia and possible protective effect of diall yl disulfide on the earache. The essential oil of garl ic diluted with edi ble first step of carcinogenesis via modulati on o f enzymes oil is administered to dogs and other pets to expel 78 in volved in carci nogen metabo li sm . parasites fro m the di gesti ve tract as well as from other parts of the body. It has also been pointed out that Garli c has also been found to modulate feeding of dogs with a teaspoonful of fresh garlic immunological response against cancer. Mice injected j uice twice a week keeps them free fro m parasites. with aqueous garlic extract-treated Ehrlich carcinoma In spite of beneficial effects of garli c again st a cell s acquire resistance against a chall enge with variety of diseases, it suffers from the di sadvantage of 79 untreated tumor cell s. In a human study, producing bad breath. Incidentall y, the constitutents admin istration of raw garli c (0.5 g per kg body wt/-. in hu man breath after ingesti on of garlic have been day) for th ree weeks induced the increase of natural analysed using proton-transfer-reacti on mass killer cell activity by 140% (Ref. 80). Diallyl spectrometry by Taucher et at. 87 and th e components sul phi de, a constituent of garl ic has been shown to have been identified as all yl methyl sulfide, inhibit carcinogen induced nuclear damage in mouse all yl methyl di sulfide, diall yl disul fide, diall yl colon epitheli al cell s and esophageal cancer in trisul fide, dimethyl sul fide and acetone. Various rats 1.82 . T he cancer preventi ve role of organosulphur preparati ons and formulations of garlic are avail able compounds of garli c has been reviewed by Sumiyoshi in the market but all of them may not be equally 83 and Wargovich . useful for all kinds o f diseases. It was observed by Essential oil of garlic known to inhibit Eric Block30 th at the ant i th romboti c principles, ajoene lipooxygenase and cyclooxygenase enzymes has also (18) and 2-vinyl-[4H]-1 ,3-dit hi in (13) are virtuall y been fo und to inhibit mouse skin tumor promo ti on. O f absent in dehydrated garlic powder, pills, oils , the di fferent components of garlic oi I tested, di- (I­ extracts and other proprietary garl ic preparati ons. It is propenyl) sulphide and ajoene have been found to presumably due to this reason that in many of th ese inhi bit both li pooxygenase and tumor p ro m o ti o n 8 ~ . preparations, essenti al o il of garlic obtained by steam Scharfenberg et at. 85 have tested the cytotoxic effect distill ati ons is used. Again many of the volatile of ajoene usin g human pri mary fibroblasts (FS 4), a compounds known to have li pooxygenase inhib itory permanent, non-tu morgeni c cell line derived from or antioxidant activity are present onl y in essential baby hamster kidney cell s (B H K 2 1) and a oils and in products prepared by appli cati on of heat. 320 INDIAN J EXP. BIOL., APRIL 2001

Thus, while essential oil of garlic lacks most of the 15 Ohaeri OC & Adoga GI, Effects of garlic oi l on body fluid antibacterial and antithrombotic activity of garlic acidity and electrolytes in experimental diabetic rats, Med Sci Res, 26 (1998) 487. extract prepared at room temperature, it appears to 16 Singh RN, Pri thi viraj B, Singh UP, Singh PK & Wagner KG , possess equally interesting antitumor and anti oxidant Effect of some pesticides and ajoene on biology of 34 properties among other types of biological activities . Telranycllfls urlicae Koch, J P/alll Dis Prol. 103 (1996) 195. Appropriate formulations of garlic for the cure of 17 Kyo E. Uda N. Suzuki A, Kakimoto M, Ushijima M. Kasuga different diseases are, therefore, a necessity. The S & Itakllra Y, Im munomodulation and antitumor acti vi ti es of aged garli c ex tract, Phylollledicine. 5 ( 1998) 259. research on garlic may go a long way in finding out 18 Bordia A. Bansa l HC, Arora SK, Singh SV, Effect of its newer therapeutic values, in validating the claims essential oil s of garlic and onion on alimen tary hyperlipemia. made in different systems of medicine and also in Alherosclerosis, 21 ( 1975) 15. assessi ng its potential in plant disease control. 19 Augusti KT, Hypocholesterolemic effect of garlic, Allilllll satiVlI1II Linn . IIIe/iGII J Exp Bio/, 15 (1977) 489. 20 Peng JP, Chen H. Qiao YQ. Ma LR, Narui T, Suzuki H. Okuyama T & Kobayashi H, Two new steroida l saponins References from Al/iulII salillulII and their inhibitory effects on blood I Sri Bhavami ra, Al/iulII salivulII, in Bhavaprakas Nighalllll coagulability. Yao Hsueh HSlleh PlIO. 31 ( 1996) 607. edited by G S Pandey (Chaukhambha Bharati Academy , 2 1 Appleton JA & Tansey MR, Inhi bition of growth of Varana i) 1995. 132. zoopathogenic fung i by garlic ex tract. Myc%gia. 67 (1975) 2 Yo hida S. Karuga S, Hayashi N, Ushiroguchi T, Matsu rra H 882. & Nakagawa S, Antifungal ac tivity of ajoene derived from 22 Moore GS & Atkins RD. Fungicidal and fingistatic effects of ga rli c, Appl Ellviroll Microbiol , 53 (1987) 615. an aqueous garlic extract on medically important yeast-like 3 Singh UP, Pandey VN, Wagner KG & Singh KP. Antifungal fungi, Mycologia, 69 ( 1977) 341. activity of ajoene, a constituent of garlic (Al/iulII salivlIlII L.), 23 Fromthing RA & Bulmer GS, /11 vilro effect of aqueous Call J BOI, 68 (1990) 1354. ex tract of garli c (AI/illlll sativlIlII) on the growth and viability 4 Kumar M & Berwal JS , Sensitivity of food pathogens to of Cryplococcus lI e% rlllans, Myc%gJ'a. 70 ( 1978) 397. garlic (AI/illlll 5alivlIIlI ), J Appl Microbiol, 84 ( 1998) 2 13. 24 Mishra SB & Dixit SN, Fungicidal spectrum of the leaf 5 Yoshida H, Iwata N. Katsuzaki H. aganawa R, Ishikawa K, extract of Al/iulII salivulII, Illdiall PhylopalllO/, 29 (I 976) 448. Fukuda H, Fujino T & Suzuki A. Antimicrobial activity of a 25 Singh UP, Path ak KK, Khare MN & Singh RB . The effect of compound iso lated from an oil-macerated garli c extract, aqueous garli c leaf extract on two pathogens. FusariulII Biosci Biolech Biochelll, 62 ( 1998) 1014. oxysporlllll f. sp. ciceri and Sc/t'I'olinia sc/eroliol'lllll. 6 Slietsuna K. Iso lation and characterization of angiotensin 1- Myc%gia. 71 ( 1979) 556. converting enzyme inhi bi tor dipeptides derived from AlliulII 26 Block E. Ahmad S, Catalfamo JL. Jai n MK & Apitz-Castro satiVlI1II (garlic), J NutI' Biochelll. 9 ( 1998) 415. R, Anti th rombotic organosulfur compounds from garlic: 7 Augusti KT & Mathew PT, Effect of long te,:m feeding of structural, mechanistic and synthetic studies. J Alii Chelll Soc. aqueous extracts of onion (Al/iulII cepa) and garli c (AlIilllll 108 (1986) 7045. salivulII ) on normal rats. Ille/iall J Exp Bioi, I I (1973) 239. 27 Cavallito CJ & Bailey lH, Allicin. the antimi crobial principle 8 Itakawa y, Inone K, Sasagawa S & Fujiwara M, Effect of S­ of AlliulII .wlilllllll L. Isolation, physical properties and methylcysteine sulfoxide, S-Allylcysteine sulfox ide and an tibacterial action, J Alii Chelll Soc. 66 ( 1944) 1950. related sulfur containing amino acids on lipid metabolism of 28 Stoll A & Seebeck E. Chemical investi gation on allicin, the experimental hypercholesterolemic rats, J Ntllr, 103 (1973) specific pri nciple of garlic. Adv Ellzymo/ Relal Subjecl 88. Biochelll, II (1951) 377. 29 Manabe T, Hasumi A, Sugiyama M, Yamazaki M & Saito K. 9 Slimiyoshi H. New Pharmacological activities of garlic and Allinase [S-Alk(en)y l-L-cysteine su lfox ide lyase] from its constitutents. Nippoll Yakllrigakll Zan-hi, 110, Suppl I AI/illlll IIIberoslllll, EliI' J Biochelll, 257 (199R) 2 1. (1997) 93. 30 Block E, The Chemistry of Garlic and Onions, Sci Alii. 252 10 Wang BH. Zuzel KA . Rah man K. Billington D. Protective (1985) 94. effects of aged garlic extract against bromobenzene toxicity 31 Whitaker JR, in Advallces ill food research, vo l. 22. edi ted by to precision cut rat liver sli ces. Toxicol, 126 (1998) 2 13. CO Chichester and 1M Mrak. GF Stewart (Academic Press. II Laland P & Havrevold OW, Zur kenntnis des per os ew York), 1976. wirksamen blutzuckersenkenden Prinzips der Zwiebeln 32 Lawson LD, Wand ZJ & Hughes BG. n-Glutamyl-S­ (AI/illlll salilllllll). Z Physiol Chelll. 221 ( 1933) 180. alkylcysteincs in garlic and other Allilllll spp.: Precursors of 12 Sheela CG & August KT, Antidiabetic effects of S-allyl age-dependent trans-I-propenyl thiosulfinates. J Nal Prod. 54 cysteine sulphox ide isolated from garlic, AlliulII salilllllll. (199 1) 436. Ille/iall J £'(P Bioi 30 ( 1992) 523. 33 Brodnitz MH , Pascale J V & Derslice LV. Flavor compounds 13 Kumari K & Augusti KT, Antidiabetic effects of S­ of garlic extract. J Agric Food Chelll. 19 ( 1971) 273. methylcysteine sulphoxide on Alloxan diabetes, Plalll Med, 34 Block E, Iyer R, Grisoni S. Saha C. Belman S & Lossing FP. 61 (1995) 72. Lipoxygenase inhibitors from essential oil of garlic. 14 Ahmed RS & Sharma SB. 13iochemi(;al studies on combined Markovnikov udditi ofl of the allyldithio radi(;al of olefins. J effects of garli c (AlliulII Sl/rilllllll Linn) and gin ger (Zillgiber Alii Chelll Soc 110 ( 1988) 7R 13. officinallf Rose) in albino rats, Indian J E).p Bioi, 35 (1997) 35 Vernin G, Mekger J, Fraisse D, & Scharff C. GS-MS (EI. 841. PCI, NC I) computer analysis of volatil e sulfur-coflJPou nds in SINGH et 01.: ROLE OF GARLIC IN HUMA & PLANT DISEASES 321

garlic essential oils. Application of the mass fragmcntometry 53 Johnson MG & Vaughn RH, Death of SallllOilel/a SIM technique, Plant M ed,50 ( 1986) 96. typlrillll/ril/l11 and Eschericlria coli in the presence of freshly 36 Suetsuna K, Isolation of peptide from garlic and reconstituted garlic and o ni on, Appl Microbiol, 17 (1969) antihypertensive agents containing the peptides as active 903. ingredients, Chelll Abslr,( 1995) 5 I 665r. 54 Delaha EC & Garaguci VF, Inhibition of mycobacteri a by 37 Mizuno M, T suchida H, Kuzukue & 'v1izuno S, Rapid garlic extract (AI/iI/III Smilil/lIl), Alltilllicrob Agents quantitative analysis and distribution of free quercetin in Clrelllotfr erap, 27 (1985) 485. vegetables and fruits, Nippoll Shokl/hin Kogyo Cukhaishi, 39 55 Firouzi R, Azadbakht M & abinedjad A. Anti-li steri al (1992) 88. activity of essential o ils of some plants. J Appl Anill/al Res. 38 Matsura H, Moritati Gokuchi T , Itakura Y & Hayashi N, 14 ( 1998) 75. Antifungal stcroid saponins from AI/iI/III, Chelll Abstr,(I990) 56 Dwivedi C. John LM. Schmidt DS & Eng ineer FN. Effccts of 1251 83z oil - soluble organosulfur compounds from garli c on 39 Uda N. Extraction of cruboside B from plant as inhibitor of doxorubicin-induced lipid peroxidatio n. Allticallce r D/'IIg, 9 carcinogens, Ch elll Abstr,( 1991 ) 108914n ( 1998) 291. 40 Barone, FE & Tansey MR. Isolatio n, purification, synthesis 57 Mathew BC, Deniel RS & Augu ti KT, Hypolipidcmi c effect and kinetics of activity of the anticandidal component of of garlic protein substituted for casien in diet of rats AI/iI/III satilll/l11 and a hypothesis for its mode of action. compared to th ose of garli c oil. Indian J Exp Bioi, 34 ( 1996) Mycologia. 69 ( 1977) 793. 337. 41 Prasad G & Sharma VD, Efficacy of garlic (AI/iI/III Sa/illl/III ) 58 Keskin E. Durgun Z. Kocabatmaz M, Bas AL, Donmez N & treatment against experimental candidiasis in chicks, Bri Vet J Onder F, Effect of garlic and aspirin on some coagulation 136 ( 1980) 448. parameters in hypercholesterolaemic rabbits, M ed Sci Res. 26 42 Caporaso ,Smith SM & Eny RHK, Antifungal activity in ( 1998) 413. human urine and serum after injestion of garlic (AI/iI/III 59 Steiner M & Lin RS, Changes in platelet function and Satilll/III ), Antilllicrob Agellts Chelllotherap, 23 ( 1983) 700. susceptibility of lipoproteins to oxidatio n associated with 43 Davis LE, Shen J & Cai Y, Antifungal activity in human administration of aged garlic extract, J Cardiollos Phamracol. cerebrospinal fluid and plasma after intravenus administration 31 ( 1998) 904. of AI/iI/III sa/ilil/Ill. Alltilllicrob Agellls Chelllotherap. 34 60 Apitz-Castro R. Cabrera S, Cruz MR, Ledezma L & Jain MK. ( 1990) 651. Effects of garli c extract and three pure compone nts isolated 44 Singh UP, Chauhan VB, Wagner KG & Kumar A. Effect of from it in human platelet aggregation, arachidonate ajoene, a compound derived from garlic (AI/illlll Sa/ilil/III ) on metabolism. release reacti on and platelet ultrastructure. Phytopht/lOra drechsleri f.sp. cajani. Mycolog ia, 84 Throll/bosis Res. 32 (1983) 155. ( 1992) I 05. 61 Block E, Ahmad S. Jain MK. Crecely RW, Apitz-Castro R & 45 Hughes BG & Lawson LD. Antimicrobial effects of AI/iI/III Cruz MR, (E, Z)-Ajoene: A potent antithrombotic agent from Satilll/l11 L. (Garlic), AI/iI/III alllpeloprasl/lII L. (Elephant garlic. J Alii Cllelll Soc, 106 (1984) 8295. Garlic) and AI/iI/III cepa L. (Oni on). garli c compounds and 62 Apitz-Castro R, Ledesma E. Escalante J & Jain MK. The commercial garlic supplcment products. Phytother Res, 5 mo lecular basis o f the antiplatelet acti o n of ajoene : direct ( 1991 ) 154. interaction w ith the fibrogen receptor, Bioclrelll Bioplrys Res 46 Reimers F. Smo lka SE. Werres S. Schumacher KP & Wagner COIIIIIIIIII, 141 ( 1986) 145. KG. 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oi l on detoxifying enzymes and mi cronuclei formation in rats 79 Fuj iwara M & Natata T, Inductio n of tumor immunity wi th treated with azoxymethane. lilt J ViI NlIIr Res, 68 ( 1998) 208. tumour cell s treated with extract of garlic (AlIiulIl sarivulII). 70 Iqbal M & Athar M, Attenuation of iron-nitrilotri acelate­ Nall/re, 2 16 ( 1967) 83. mediated re nal oxidatine stress, tox ICity and 80 Kandil OM, Abdullah T H & Elkadi A, Garl ic and the hyperpro li fe rati ve response by the prophylacti c treatment of immune system in human: it s effect on natural ki ll er cells, rats wi th garlic oil. Food Chelll Toxicol, 36 ( 1998) 485. Fed Proc, 46 (1987) 44 1. 8 1 Wargovich MI & Gold berg MT, Diallylsulfide : A natura lly 71 Lau B, in Garli c research update (Odyssey Publishing Inc. occurring thioether that inhibi ts carcinogen induced nuclear Canada V6M 2J2). ( 1991 ) 15. damage to colon epithe li al cells ill vivo, MUlal Res, 143 72 Fenwick GR & Hanley AB. The genus AlliulII -Part I, Cril Rev ( 1985) 127. Food Sci, 22 (1 985) 199. 82 Wargovich MI. Woods C, Eng VWS, Stephens LC & Gray 73 Mori oka N, Sze LL, Morton DL & Irie RF, A protein fracti on KM, Chemoprevention of nitrosomethyl benzylamine fro m agcd garli c extract enhances cytotoxicity and induced esophageal cancer in rats by the thioether di altyl proliferati on of human lymphocytes mediated by interl eukin- sul fi de. Call cer Res, 48 ( 1988) 6872. 2 and concanavalin A, Callcer 1111111 1/1101 fllllllull olhemp. 37 83 Sumiyoshi H & Wargovich MJ, Garl ic (AlliulIl .I'alivulII ) : A ( 1993) 3 16. review of its relatio nship to cancer, Asia Pacific J Pharlllacol, 74 Criss WE, Fakunle J, Knight E, Adkins J, Mo rri s HP & 4 ( 1989) 133. Dh ill on G. Inhibition of tumor growth w ith low di etary 84 Belman S, Solomon J, Segal A, Block E & Barany G, protein and di etary garli c extracts. Fed Proc, 4 1 ( 1982) 28 1. Inhi bition of soybean lipooxygenase alld mouse skin tumor 75 Lau BHS, Woll ey JL, Marsh CL. Barker GR, Koobs DH & formati on by oni o n and garl ic components. J Biochelll Torrey RR. Superi orit y of intralesional immunoth erapy with Toxicol, 4 ( 1989) 15 1. CyallobacleriulIl parvulIl and AlliulIl salivUIIl in cont rol of 85 Scharfe nberg K, Wagner R & Wagner KG, The cytotoxic murine transitio nal cell carcinoma, J Urol, 136 ( 1986) 701. effect of ajoene, a natu ral product from garlic, investi gated 76 Belm an S, Onio n and garlic o il s inhibit tumor promoti o n, with different ce lt lines, Callcer Lell, 53 (1990) 103. Carcillogell esis.4 (1983) 1063. 77 Chen GW, Chung JG. Hsieh C L & Lin JG, Effect. of the 86 Zheng OX, Zhang SQ, Zhao S, Min 1M, Wang K & Liu SL, garli c components diallysul fide and diall yldi sulfide on Z-aj oene induces tumor celt s to die by apoptosis, Chillese Sci arylamine N-acetyl transferase acti vity in human colon tumor Bull, 43 ( 1998) 11 35. cell s, Food Chelll Toxicol, 36 (1998) 76 1. 87 Taucher 1, Hansel H, Jordan A & Lindinger W, Analysis of 78 Siess MH. LeBon AM, Canive nc-Lavier MC & Suschetet M, compound in human breath after ingestion of garl ic usi ng Modification of hepatic drug-metabolizi ng enzymes in rats proton-transfer-reacti on mass spectrometry. J Agric Food treated wit h alky lsullides, Callcer Lell, 120 ( 1997) 195. Chelll , 44 (1 997) 377 8.