1: J Nutr 2001 Mar;131(3s):989S-93S 
Cholesterol-lowering effect of garlic extracts and organosulfur compounds: human and animal studies. Yeh YY, Liu L. Department of Nutrition, The Pennsylvania State University, University Park, PA 16802, USA. yyy1@psu.edu 
The medicinal use of garlic dates back thousands of years, but there was little scientific support of its therapeutic and pharmacologic properties until recently. In the past decade, the cancer-protective effects of garlic have been well established by epidemiologic studies and animal experiments. However, the cardiovascular-protective properties of garlic are less well understood. In particular, despite the reported hypocholesterolemic effect of garlic, the mechanism of the effect is unclear. In a recent randomized, double-blind, placebo-controlled intervention study, we showed that aged garlic extract (AGE) supplementation was effective in lowering plasma concentration of total cholesterol by 7% and LDL cholesterol by 10% in hypercholesterolemic men compared with subjects consuming a placebo. Supplementation of AGE in animal diets similarly reduced plasma concentrations of total cholesterol and triacylglycerol by 15 and 30%, respectively. In subsequent experiments using cultured rat hepatocytes, we found 44--87% inhibition of cholesterol synthesis by the water-extractable fraction (WEF), methanol-extractable fraction (MEF) and petroleum ether-extractable fraction (PEF) of fresh garlic, and Kyolic (liquid form of AGE). These observations suggested that hydrophilic and hydrophobic compounds of garlic are inhibitory to cholesterol synthesis. Because 
S-allylcysteine (SAC) alone was less potent than Kyolic, which contains SAC and other sulfur compounds, a maximal inhibition appears to require a concerted action of multiple compounds of garlic. In a series of experiments, we further characterized the inhibitory potency of individual water-soluble and lipid-soluble compounds of garlic. Among water-soluble compounds, SAC, 
S-ethylcysteine (SEC), and S-propylcysteine (SPC) inhibited cholesterol synthesis by 40--60% compared with 20--35% by gamma-glutamyl-S-allylcysteine (GSAC), gamma-glutamyl-S-methylcysteine (GSMC) and gamma-glutamyl-S-propylcysteine (GSPC). Lipid-soluble sulfur compounds (i.e., diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl sulfide and dipropyl trisulfide) at low concentrations (0.05--0.5 mol/L) slightly (10--15%) inhibited cholesterol synthesis but became highly cytotoxic at high concentrations (1.0--4.0 mol/L). All water-soluble compounds, except 
S-allylmercaptocysteine, were not cytotoxic, judging from the release of cellular lactate dehydrogenase into the culture medium. Taken together, the results of our studies indicate that the cholesterol-lowering effects of garlic extract, such as AGE, stem in part from inhibition of hepatic cholesterol synthesis by water-soluble sulfur compounds, especially SAC. 
Publication Types:
Review
Review, tutorial 
PMID: 11238803 [PubMed - indexed for MEDLINE]


2: Lipids 2000 Feb;35(2):197-203 
Inhibition of cholesterol biosynthesis by organosulfur compounds derived from garlic. 
Liu L, Yeh YY. 
Graduate Program in Nutrition, The Pennsylvania State University, University Park 16802, USA. 
The study was undertaken to test the inhibitory potential on cholesterogenesis of organosulfur compounds derived from garlic. The primary rat hepatocytes maintained in Dulbecco's modified Eagle's medium were treated with [2-14C]acetate as substrate for cholesterol synthesis in the presence or absence of test compounds at 0.05 to 4.0 mmol/L. Eleven water-soluble and six lipid-soluble compounds of garlic were tested. Among water-soluble compounds, 
S-allyl cysteine (SAC), S-ethyl cysteine (SEC), and S-propyl cysteine (SPC) inhibited [2-14C]acetate incorporation into cholesterol in a concentration-dependent manner, achieving 42 to 55% maximal inhibition. Gamma-glutamyl-S-allyl cysteine, gamma-glutamyl-S-methyl cysteine, and gamma-glutamyl-S-propyl cysteine were less potent, exerting only 16 to 29% maximal inhibitions. Alliin, S-allyl-N-acetyl cysteine, S-allylsulfonyl alanine, and S-methyl cysteine had no effect on cholesterol synthesis. Of the lipid-soluble compounds, diallyl disulfide (DADS), diallyl trisulfide (DATS), and dipropyl disulfide (DPDS) depressed cholesterol synthesis by 10 to 25% at low concentrations (< or =0.5 mmol/L), and abolished the synthesis at high concentrations (> or =1.0 mmol/L). Diallyl sulfide, dipropyl sulfide, and methyl allyl sulfide slightly inhibited [2-14C]acetate incorporation into cholesterol only at high concentrations. The complete depression of cholesterol synthesis by DADS, DATS, and DPDS was associated with cytotoxicity as indicated by marked increase in cellular LDH release. There was no apparent increase in LDH secretion by water-soluble compounds except S-allyl mercaptocysteine, which also abolished cholesterol synthesis. Judging from maximal inhibition and IC50 (concentration required for 50% of maximal inhibition), SAC, SEC, and SPC are equally potent in inhibiting cholesterol synthesis. 
PMID: 10757551 [PubMed - indexed for MEDLINE]


3: J Cell Biochem Suppl 1997;

27:100-5 
Cancer prevention by organosulfur compounds from garlic and onion. Fukushima S, Takada N, Hori T, Wanibuchi H. Department of Pathology, Osaka City University Medical School, Japan. Environmental compounds are known to be involved in both the generation and prevention of many human cancers. It is important to discover naturally occurring or synthetic compounds which can block the process of carcinogenesis. We have focused attention on several organosulfur compounds (OSCs) in garlic and onion, and analyzed their potential for chemoprevention in the post-initiation stage in a liver medium-term bioassay (Ito test) and a multi-organ carcinogenesis bioassay. In the ITO test, rats were given diethylnitrosamine (DEN), 200 mg/kg b.w., i.p.; starting 2 weeks later they were treated with test chemicals for 6 weeks and then killed. All rats were subjected to 2/3 hepatectomy 1 week after the start of test chemical treatment. Inhibitory effects of a number of compounds could be identified in terms of reduced numbers and areas of liver glutathione S-transferase placental (GST-P) positive foci. In the multi-organ carcinogenesis bioassay, rats were given DEN, N-methyl-N-nitrosourea, N-butyl-N-(4-hydroxybutyl)nitrosamine, N,N'-dimethylhydrazine, and dihydroxy-dipropylnitrosamine during the first 4 weeks, followed by test chemicals for 24 weeks. Various organs were examined. As a result, oil-soluble OSCs such as methyl propyl disulfide and propylene sulfide demonstrated inhibitory effects on the development of GST-P positive foci. Moreover, water-soluble OSCs such as S-methylcysteine and cysteine similarly decreased GST-P focus formation. In contrast, OSCs such as diallyl sulfide, diallyl trisulfide, and allyl methyl trisulfide enhanced formation of such altered hepatocellular foci. Inhibitory potential for colon and renal carcinogenesis was observed in rats treated with diallyl disulfide. Thus, the results indicate that some OSCs exert chemopreventive effects on chemical carcinogenesis. It must, however, be borne in mind that they may also demonstrate promotion potential, depending on the organ examined. Publication Types: Review 
Review, tutorial 
PMID: 9591199 [PubMed - indexed for MEDLINE]


4: Cancer Lett 1997 Sep 16;118(1):61-7 
Mechanism of differential efficacy of garlic organosulfides in preventing benzo(a)pyrene-induced cancer in mice. Srivastava SK, Hu X, Xia H, Zaren HA, Chatterjee ML, Agarwal R, Singh SV. Mercy Cancer Institute, Mercy Hospital of Pittsburgh, PA 15219, USA. The mechanism of differential efficacies of diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), dipropyl sulfide (DPS) and dipropyl disulfide (DPDS) in preventing benzo(a)pyrene (BP)-induced cancer in mice has been investigated by determining their effects on the enzymes of BP activation/inactivation pathways. With the exception of DATS, treatment of mice with other organosulfides (OSCs) caused a small but significant increase (37-44%) in hepatic ethoxyresorufin O-deethylase (EROD) activity. However, the forestomach EROD activity did not differ significantly between control and treated groups. Only DAS treatment caused a modest but statistically significant reduction (about 25%) in pulmonary EROD activity. These results suggest that while reduction of EROD activity may, at least in part, contribute to the DAS-mediated inhibition of BP-induced lung cancer, anticarcinogenic effects of OSCs against BP-induced forestomach carcinogenesis seems to be independent of this mechanism. Treatment of mice with DAS, DADS and DATS resulted in a significant increase, as compared with control, in both hepatic (3.0-, 3.2- and 4.4-fold, respectively) and forestomach (1.5-, 2.7- and 2.7-fold, respectively) glutathione transferase (GST) activity toward 
anti-7beta,8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE), which is the ultimate carcinogen of BP. The pulmonary GST activity was not increased by any of the OSCs. Even though epoxide hydrolase (EH) activity was differentially altered by these OSCs, a correlation between chemopreventive efficacy of OSCs and their effects on EH activity was not apparent. The results of the present study suggest that differences in the ability of OSCs to modulate GST activity toward anti-BPDE may, at least in part, account for their differential chemopreventive efficacy against BP-induced cancer in mice. PMID: 9310261 [PubMed - indexed for MEDLINE] 

5: J Natl Med Assoc 1996 Nov;88(11):694, 704 In vitro efficacy of a compound derived from garlic against Pneumocystis carinii. 
Abdullah TH.
Publication Types:
Letter 
PMID: 8999132 [PubMed - indexed for MEDLINE]


6: Ann Soc Belg Med Trop 1994 Mar;74(1):51-9 
Antiparasitic activity of diallyl trisulfide (Dasuansu) on human and animal pathogenic protozoa (Trypanosoma sp., Entamoeba histolytica and Giardia lamblia) in vitro. 
Lun ZR, Burri C, Menzinger M, Kaminsky R. Swiss Tropical Institute, Basel. 
Garlic (Allium sativum L.) and one of its major components, allicin, have been known to have antibacterial and antifungal activity for a long time. Diallyl trisulfide is a chemically stable final transformation product of allicin which was synthesized in 1981 in China and used for treatment of bacterial, fungal and parasitic infections in man. The activity of diallyl trisulfide was investigated in several important protozoan parasites in vitro. The IC50 (concentration which inhibits metabolism or growth of parasites by 50%) for Trypanosoma brucei brucei, T.b. rhodesiense, T.b. gambiense, T. evansi, T. congolense and T. equiperdum was in the range of 0.8-5.5 micrograms/ml. IC50 values were 59 micrograms/ml for Entamoeba histolytica and 14 micrograms/ml for Giardia lamblia. The cytotoxicity of the compound was evaluated on two fibroblast cell lines (MASEF, Mastomys natalensis embryo fibroblast and HEFL-12, human embryo fibroblast) in vitro. The maximum tolerated concentration for both cell lines was 25 micrograms/ml. The results indicate that the compound has potential to be used for treatment of several human and animal parasitic diseases. PMID: 8024350 [PubMed - indexed for MEDLINE] 

7: J Tongji Med Univ 1994;14(3):142-7 Effect of diallyl trisulfide on the activation of T cell and macrophage-mediated cytotoxicity. 
Feng ZH, Zhang GM, Hao TL, Zhou B, Zhang H, Jiang ZY. Department of Medical Molecular Biology, Tongji Medical University, Wuhan. At high concentration (50 micrograms/ml), diallyl trisulfide (DATS) had an inhibitory effect on T cell activation (compared with control group, P < 0.05). But at appropriate concentrations (3.125-12.5 micrograms/ml), DATS augmented the activation of T lymphocytes by Con A (compared with control group, P < 0.01). The augmentation of T cell activation by DATS was related to its inhibitory effect on the production of nitric oxide (NO) by macrophages. In a wide range of concentrations (1-100 micrograms/ml), DATS can inhibit the production of NO by macrophages (P < 0.05, P < 0.01). In addition, DATS can antagonize the inhibition of tumor-derived immunosuppressive factors produced by S180 cells and Ehrlich ascitic cancer cells on the activation of T cells, and reduce the inhibitory rate significantly (P < 0.01). DATS, despite its inhibition of the production of NO by macrophages, can significantly enhance the production of hydrogen peroxide (H2O2) by macrophages. When macrophages were pretreated with DATS for 24 h, the cytotoxicity % of macrophages to three tumor cell lines was significantly higher than that in corresponding control group (P < 0.05, P < 0.01). In the presence of both DATS and LPS, the cytotoxicity of macrophages was further enhanced so that the cytotoxicity % of macrophages to tumor cells was significantly higher than either that in the presence of DATS alone or that in the presence of LPS alone (P < 0.05, P < 0.01). These results indicate that DATS can augment the activation of T cells and enhance the anti-tumor function of macrophage, suggesting that DATS may be potentially useful in tumor therapy. PMID: 7807598 [PubMed - indexed for MEDLINE] 

8: Cancer Lett 1993 Oct 15;74(1-2):85-90 Impact of organosulfur compounds in garlic on canine mammary tumor cells in culture. Sundaram SG, Milner JA. 
Department of Nutrition, Pennsylvania State University, University Park 
16802. 
Six organosulfur compounds found in garlic were examined for their ability to alter the growth of canine mammary tumor cells (CMT-13) in culture. Water-soluble organosulfur compounds (S-allyl-cysteine, S-ethyl-cysteine and 
S-propyl-cysteine) did not significantly alter the growth of CMT-13 cells when added to cultures at 1.0 mM or less. However, oil-soluble organosulfur compounds (diallyl sulfide, diallyl disulfide and diallyl trisulfide) markedly inhibited growth. Increasing addition of diallyl disulfide (DADS) resulted in a progressive decrease in CMT-13 cell growth. Addition of glutathione before DADS markedly decreased the severity of the growth inhibition. Treatment with DL-buthionine-SR-sulfoxamine, a specific inhibitor of glutathione synthesis, accentuated the growth inhibition caused by DADS. These studies show that some organosulfur compounds found in garlic are effective inhibitors of the growth of the neoplastic CMT-13 cell. The inhibitory effects of these compounds are modified by intracellular glutathione. 
PMID: 8287376 [PubMed - indexed for MEDLINE]


9: Planta Med 1992 Oct;58(5):417-23 
In vitro virucidal effects of Allium sativum (garlic) extract and compounds. 
Weber ND, Andersen DO, North JA, Murray BK, Lawson LD, Hughes BG. Department of Microbiology, Brigham Young University, Provo, Utah 84602. Garlic (Allium sativum) has been shown to have antiviral activity, but the compounds responsible have not been identified. Using direct pre-infection incubation assays, we determined the in vitro virucidal effects of fresh garlic extract, its polar fraction, and the following garlic associated compounds: diallyl thiosulfinate (allicin), allyl methyl thiosulfinate, methyl allyl thiosulfinate, ajoene, alliin, deoxyalliin, diallyl disulfide, and diallyl trisulfide. Activity was determined against selected viruses including, herpes simplex virus type 1, herpes simplex virus type 2, parainfluenza virus type 3, vaccinia virus, vesicular stomatitis virus, and human rhinovirus type 2. The order for virucidal activity generally was: ajoene > allicin > allyl methyl thiosulfinate > methyl allyl thiosulfinate. Ajoene was found in oil-macerates of garlic but not in fresh garlic extracts. No activity was found for the garlic polar fraction, alliin, deoxyalliin, diallyl disulfide, or diallyl trisulfide. Fresh garlic extract, in which thiosulfinates appeared to be the active components, was virucidal to each virus tested. The predominant thiosulfinate in fresh garlic extract was allicin. Lack of reduction in yields of infectious virus indicated undetectable levels of intracellular antiviral activity for either allicin or fresh garlic extract. Furthermore, concentrations that were virucidal were also toxic to HeLa and Vero cells. Virucidal assay results were not influenced by cytotoxicity since the compounds were diluted below toxic levels prior to assaying for infectious virus. These results indicate that 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.(ABSTRACT TRUNCATED AT 250 WORDS) 
PMID: 1470664 [PubMed - indexed for MEDLINE]



10: J Toxicol Environ Health 1992 Sep;37(1):1-9 
Inhibition of benzo[a]pyrene-induced bone marrow micronuclei formation by diallyl thioethers in mice. 
Marks HS, Anderson JL, Stoewsand GS. 
Department of Food Science and Technology, New York State Agricultural Experiment Station, Cornell University, Geneva. Diallyl thioethers (DATEs), naturally occurring compounds present in garlic, were investigated for their putative ability to inhibit benzo[a]pyrene-induced genotoxicity in ICR and C3H strains of mice. The mouse bone marrow micronucleus assay was used as an indicator of in vivo genotoxicity. A dose of 0.67 mmol total DATEs/kg body weight inhibited formation of micronucleated polychromatic erythrocytes (MPCEs) by 24%, and 0.33 mmol DATEs inhibited formation of MPCEs by 45%. Possibly the toxicity of DATEs accounted for less inhibition with the higher dose. Formation of MPCEs were inhibited only slightly by DATEs in C3H mice. These results indicate that the mouse bone marrow micronucleus assay can be used to identify organosulfur components of garlic that inhibit genotoxicity. 
PMID: 1522606 [PubMed - indexed for MEDLINE]

11: J Nutr 2001 Mar;131(3s):1058S-60S 
Antiproliferative effects of allium derivatives from garlic. Pinto JT, Rivlin RS. 
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. pintoj@mskcc.org 
There is increasing evidence that allium derivatives from garlic have significant antiproliferative actions on human cancers. Both hormone-responsive and hormone-unresponsive cells lines respond to these derivatives. The effects shown by allium derivatives include induction of apoptosis, regulation of cell cycle progression and modification of pathways of signal transduction. Allium derivatives appear to regulate nuclear factors involved in immune function and inflammation, as well as in cellular proliferation. Our own studies indicate that allium derivatives inhibit proliferation of the human prostate cancer cell line (LNCaP) and the human breast cancer cell line (MCF-7). Further research is required to clarify the mechanisms of inhibition of cellular proliferation by allium derivatives and to explore their potential application to cancer prevention and control. Publication Types: Review 
Review, tutorial 
PMID: 11238816 [PubMed - indexed for MEDLINE]

12: J Nutr 2001 Mar;131(3s):1041S-5S 
Mechanisms of inhibition of chemical toxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic. Yang CS, Chhabra SK, Hong JY, Smith TJ. 
Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA. csyang@rci.rutgers.edu 
Diallyl sulfide (DAS) is a flavor compound derived from garlic and is sequentially converted to diallyl sulfoxide (DASO) and diallyl sulfone (DASO(2)) by cytochrome P(450) 2E1 (CYP2E1). These compounds have been shown to reduce the incidence of a multitude of chemically induced tumors in animal models. The impediment of phase I activation of these carcinogens is hypothesized to be accountable for the reduction in tumor incidence. Indeed, DAS, DASO and DASO(2) are competitive inhibitors of CYP2E1. DASO(2), in addition, is a suicide inhibitor of CYP2E1. These compounds have been shown to reduce carbon tetrachloride-, N-nitrosodimethylamine- and acetaminophen-induced toxicity in rodents. All three chemicals are substrates for CYP2E1. The protective effect was observed when the organosulfur compounds were given before, during or soon after chemical treatment. DAS and DASO(2) inhibited the bioactivation of 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and related lung tumorigenesis in A/J mice. Because CYP2E1 does not play a key role in NNK activation, the inhibition of other CYP enzymes active in NNK metabolism is likely. DAS also has been shown to induce other CYP and phase II enzymes as well as decrease hepatic catalase activity. All of these effects are observed at concentrations much higher than what is normally ingested by humans. The biological activities of garlic and its related compounds at lower concentrations that mimic human consumption remain to be studied further. 
Publication Types:
Review
Review, tutorial 
PMID: 11238812 [PubMed - indexed for MEDLINE]

13: J Nutr 2001 Mar;131(3s):1027S-31S 
A historical perspective on garlic and cancer. Milner JA. Nutrition Department, The Pennsylvania State University, University Park, PA 16802, USA. 
Epidemiological and laboratory studies provide insight into the anticarcinogenic potential of garlic and its constituent compounds. Both water- and lipid-soluble allyl sulfur compounds are effective in blocking a myriad of chemically induced tumors. Part of the protection from these compounds probably relates to a block in nitrosamine formation and metabolism. However, blockage in the initiation and promotion phases of the carcinogenicity of various compounds, including polycyclic hydrocarbons, provide evidence that garlic and its constituents can alter several phase I and II enzymes. Their ability to block experimentally induced tumors in a variety of sites including skin, mammary and colon, suggests a general mechanism of action. Changes in DNA repair and in immunocompetence may also account for some of this protection. Some, but not all, allyl sulfur compounds can also effectively retard tumor proliferation and induce apoptosis. Changes in cellular thiol and phosphorylation stains may account for some of these antitumorigenic properties. The anticarcinogenic potential of garlic can be influenced by several dietary components including specific fatty acids, selenium, and vitamin A. Since garlic and its constituents can suppress carcinogen formation, carcinogen bioactivation, and tumor proliferation it is imperative that biomarkers be established to identify which individuals might benefit most and what intakes can occur with ill consequences. 
Publication Types:
Review
Review, tutorial 
PMID: 11238810 [PubMed - indexed for MEDLINE]

15: Drug Metabol Drug Interact 2000;17(1-4):23-49 
Effect of organosulfur compounds from garlic and cruciferous vegetables on drug metabolism enzymes. 
Smith TJ, Yang CS. 
Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia 29208, USA. smithtj@pharm.sc.edu The frequent consumption of cruciferous vegetables and garlic is associated with several health benefits. These foods contain organosulfur compounds that are known to affect the biotransformation of xenobiotics, and therefore can influence the toxicity and carcinogenicity of environmental chemicals. In this article, we review the effects of isothiocyanates and diallyl sulfide on xenobiotic metabolism and the enzymes involved in the process. Isothiocyanates and diallyl sulfide can modulate the levels of phase I and phase II drug-metabolizing enzymes by affecting the transcriptional rates of their genes, the turnover rates of specific mRNAs or enzymes, or the enzyme activity. These compounds are not general enzyme inhibitors or inducers. They elicit selectivity in their mode of action. Elucidating the mechanisms involved in the alteration of drug-metabolizing enzymes by isothiocyanates and diallyl sulfide will increase our understanding of their possible effects on the biotransformation of drugs as well as the potential beneficial or detrimental effects of these organosulfur compounds. Publication Types: 
Review
Review, tutorial 
PMID: 11201297 [PubMed - indexed for MEDLINE]

16: Res Commun Mol Pathol Pharmacol 1998 Nov;102(2):163-74 
Mechanisms of the preventive properties of some garlic components in the carbon tetrachloride-promoted oxidative stress. Diallyl sulfide; diallyl disulfide; allyl mercaptan and allyl methyl sulfide. Fanelli SL, Castro GD, de Toranzo EG, Castro JA. Centro de Investigaciones Toxicologicas, CITEFA/CONICET, Buenos Aires, Argentina. 
Previous studies evidenced that garlic extracts and/or garlic components were able to prevent against chemically induced tumors or acute toxic effects of chemicals (e.g. CCl4 induced liver injury). The chemopreventive potential of garlic has been attributed to the presence in it of several bioactive organosulfur compounds. Those components might act as antioxidants able to scavenge free radicals. In the present work we describe initial studies on the antioxidative-stress properties of some garlic components such as: diallyl disulfide (DDS), diallyl sulfide (DAS), allyl mercaptan (AMT) and allyl methyl sulfide (AMS). We found that DAS, DDS and AMT but not AMS were able to trap trichloromethyl and trichloromethylperoxyl free radicals. Further, DDS but not DAS or AMT also inhibited CCl4 promoted liver microsomal lipid peroxidation. DAS, but not DDS, AMT or AMS was able to react with free radicals arised during UVC activation of hydrogen peroxide or terbutyl hydroperoxide but not with those produced during UVC activation of terbutyl peroxide. However, all garlic components tested absorbed energy from UVC and became partially destroyed in the process. AMT, but not DDS, AMS or DAS was able to destroy 4-hydroxynonenal, a key reactive aldehyde produced during lipid peroxidation. AMT and DDS were also able to prevent UVC plus CCl4 promoted oxidation of albumin in vitro, but DAS and AMS failed to do so. Results suggest that the antioxidative stress properties of garlic might result from the contributions of its sulfur component in different steps and not necessarily from the contribution of only one of them. 
PMID: 10100508 [PubMed - indexed for MEDLINE]

17: Biomed Environ Sci 1998 Sep;11(3):258-63 
Antitumor activity of diallyl sulfide in two-stage mouse skin model of carcinogenesis. 
Singh A, Shukla Y. 
Laboratory of Environmental Carcinogenesis, Industrial Toxicology Research Centre, Lucknow, India. 
It has been reported that diallyl sulfide (DAS), a sulfur-containing volatile compound in garlic (Allium sativum), exerts anticarcinogenic activity in various rodent tumor models. In the present study, the antitumor property of DAS was tested in Swiss albino mice in the two stage initiation-promotion mouse skin carcinogenesis. Skin cancers were initiated topically with a single subcarcinogenic dose (52 micrograms) of 7, 12-dimethyl benz (a) anthracene (DMBA). Promotion was performed by twice weekly applications of 
12-O-tetradecanoyl phorbol-13-acetate (TPA) at a dose of 5 micrograms/animal for 32 weeks. DAS was applied topically (250 micrograms/animal) thrice weekly for 3 weeks for anti-initiating and 1 h prior to each promotion treatment for anti-promoting studies. The results showed that the treatment schedule of DAS can effectively delay the onset of tumorigenesis and reduce the cumulative number of tumors and the average number of tumors per mouse. In groups in which DAS applied prior to initiation or promotion, a significant population of the animals remained tumor-free till the termination of experiment. These findings suggest that DAS can effectively inhibit chemically induced mouse skin carcinogenesis. 
PMID: 9861485 [PubMed - indexed for MEDLINE]


 20: Cancer Lett 1997 Mar 19;114(1-2):131-4 In vivo antigenotoxic effects of dietary allyl sulfides in the rat. Le Bon AM, Roy C, Dupont C, Suschetet M. Unite de Toxicologie Nutritionnelle, INRA, Dijon, France. The effects of dietary administration of diallyl sulfide (DAS), diallyl disulfide (DADS) and allyl mercaptan (AM) on the genotoxicity of different chemicals were studied in two experimental systems: (i) measurement of hepatic DNA single-strand breaks induced in rats by aflatoxin B1 (AFB1), N-nitrosodimethylamine (NDMA) or methylnitrosourea (MNU); (ii) mutagenicity of AFB1 or NDMA on Salmonella typhimurium TA100 using hepatic S9 from rats fed allyl sulfides as the activation system. All compounds strongly reduced hepatic DNA breaks induced by AFB1 and NDMA but did not modify the genotoxicity of MNU. In the Ames test, the mutagenicity of NDMA was strongly inhibited by hepatic S9 from rats fed either compound. The mutagenicity of AFB1 was also reduced but to a lesser extent. Such effects are likely related to the modulation of drug-metabolizing enzymes which play a key role in metabolic activation as well as detoxication of NDMA and AFB1. PMID: 9103271 [PubMed - indexed for MEDLINE] 

21: Toxicol Appl Pharmacol 1997 Jan;142(1):201-7 Late dimethyl sulfoxide administration provides a protective action against chemically induced injury in both the liver and the kidney. Lind RC, Gandolfi AJ. 
Department of Anesthesiology, College of Medicine, University of Arizona, Tucson 85724-5114, USA. 
Dimethyl sulfoxide (DMSO) can protect the liver from injury produced by a variety of hepatotoxicants when administered prior to or concomitant with the toxicants. This protective action has previously been attributed to DMSO-induced inhibition of bioactivation of the compounds to toxic intermediates. In these studies, the ability of DMSO to provide protection when administered 10 hr after a toxicant was evaluated in several animal models of xenobiotic-induced liver and kidney injury. In the guinea pig model of halothane-associated hepatotoxicity, male outbred Hartley guinea pigs received 2 ml/kg DMSO 10 hr after an inhalation exposure to 1.0% halothane, 40% O2 for 4 hr. DMSO decreased the extent of liver necrosis as indicated by a threefold decrease in plasma alanine aminotransferase activity 48 hr after exposure and a reduction in the incidence and extent of zone 3 necrosis. These results do not appear to be due to alterations in halothane biotransformation since DMSO administered at 10 hr after halothane had no affect on plasma concentrations of the halothane metabolite tritluoroacetic acid or covalent binding by reactive halothane biotransformation intermediates to hepatic protein. In addition, administration of the structurally analogous biotransformation inhibitor diallyl sulfide at 10 hr after halothane also had no affect on biotransformation or covalent binding but provided no protection from liver injury. Hepatic glutathione concentrations in the guinea pigs 24 hr after halothane exposure were also unaffected by late treatment with DMSO. Further studies in male Sprague-Dawley rats demonstrated the ability of DMSO to decrease the hepatic injury resulting from oral administration of 1.0 ml/kg chloroform or 0.5 ml/kg bromobenzene when administered 10 hr after either toxicant. The chloroform-treated rats also developed renal tubular necrosis with large increases in plasma creatinine and urea nitrogen, which were completely ameliorated by DMSO. Elucidating the mechanism(s) of this protective action of late DMSO administration should provide insight into the cascade of events that lead to liver and kidney injury from toxicants and, hopefully, therapeutic modalities for individuals suffering from acute, progressing, xenobiotic-induced hepatitis. 
PMID: 9007050 [PubMed - indexed for MEDLINE]

22: Biochem Pharmacol 1995 Dec 22;50(12):2099-104 
The chemopreventive agent diallyl sulfide. A structurally atypical phenobarbital-type inducer. 
Dragnev KH, Nims RW, Lubet RA. 
Laboratory of Comparative Carcinogenesis, NCI-Frederick Cancer Research and Development Center, MD 21702-1201, USA. Diallyl sulfide (DAS), a known chemopreventive agent, was administered i.g. (200 or 500 mg/kg body wt/day) to male F344/NCr rats for 4 days. Livers were removed, and hepatic levels of a variety of drug-metabolizing enzymes were determined with either catalytic assays or by quantifying levels of total cellular RNA coding for the individual genes of interest. The high dose of DAS induced the cytochrome P450 (CYP) 2B subfamily to near maximal levels [i.e. similar to those induced by phenobarbital (PB)] and induced the CYP3A subfamily, while having minimal effects on the levels of the CYP1A subfamily. In addition, DAS induced the glutathione S-transferase alpha subfamily, the glutathione S-transferase mu subfamily, and epoxide hydrolase. Unlike PB, however, DAS was also able to induce quinone oxidoreductase. In fact, the pleiotropic hepatic response to DAS appeared to be similar to that elicited by PB, with the exception that only DAS induced quinone oxidoreductase. Finally, we determined that DAS induced the levels of a specific nuclear binding protein that appears to be associated with the induction of various genes that are part of the pleiotropic response caused by PB-type inducers. PMID: 8849338 [PubMed - indexed for MEDLINE]

23: Jpn J Cancer Res 1994 Dec;85(12):1214-9 Chemopreventive effects of beta-carotene, alpha-tocopherol and five naturally occurring antioxidants on initiation of hepatocarcinogenesis by 
2-amino-3-methylimidazo[4,5-f]quinoline in the rat. Tsuda H, Uehara N, Iwahori Y, Asamoto M, Iigo M, Nagao M, Matsumoto K, Ito M, Hirono I. Chemotherapy Division, National Cancer Center Research Institute, Tokyo. Inhibitory effects of naturally occurring antioxidants on the initiation stage of hepatocarcinogenesis were studied. Group 1 rats were given a diet containing beta-carotene (beta-CT, 0.02%), alpha-tocopherol (alpha-TP, 1.5%), glutathione (GLT, 5%), vanillin (VNL, 1%), quercetin (QCT, 1%) or ellagic acid (ELA, 1%), or 3 doses of diallyl sulfide (DAS, 200 mg/kg, i.g.) over an 8-day period. On day 7, the animals received a single dose of 2-amino-3-methylimidazo[4,5-f] quinoline (IQ, 100 mg/kg, i.g.), 12 h after two-thirds partial hepatectomy for initiation and 2 weeks thereafter, were placed on promotion regimen comprising phenobarbital (0.05% in diet) and a single dose of D-galactosamine (100 mg/kg, 
i.p.). Groups 2 and 3 were treated as described for Group 1, but without test material or IQ, respectively. Survivors were killed at week 11 and antioxidant influence was assessed by comparing values for preneoplastic glutathione 
S-transferase placental form-positive (GST-P+) foci between Groups 1 and 
2. All lesions larger than 70 microns in diameter consisting of approximately 5 cells in cross section were counted. Numbers of GST-P+ foci/cm2 in Group 1 were: beta-CT, 7.99; alpha-TP, 8.21; GLT, 9.71; DAS, 10.37; VNL, 10.57; QCT, 11.1; ELA, 12.5 (n = 11-15). All, except ELA, showed a significant decrease as compared with the Group 2 value of 14.54 (n = 15). Only beta-CT showed a significant decrease for the area value. This is the first report to show that beta-CT, alpha-TP, GLT, DAS, VNL, QCT exert inhibitory effects on initiation of hepatocarcinogenesis by the food carcinogen IQ, suggesting that these antioxidants might find application as chemopreventive agents. Furthermore, the current protocol proved practical for the assessment of chemopreventive agents within 11 weeks, a relatively short period. PMID: 7852184 [PubMed - indexed for MEDLINE] 

24: Adv Exp Med Biol 1994;354:113-22 Inhibition of tumorigenesis by chemicals from garlic and tea. Yang CS, Wang ZY, Hong JY. 
Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, NJ 08855. 
Publication Types:
Review
Review, tutorial 
PMID: 8067280 [PubMed - indexed for MEDLINE]


25: Prev Med 1993 Sep;22(5):712-22 
Highlights of the cancer chemoprevention studies in China. Han J. Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing. 
New retinoids have been synthesized and screened in the search for chemopreventive agents of cancer. N-4-(Carboxyphenyl) retinamide showed a significant inhibitiory effect on carcinogenesis of cancers in the buccal pouch of hamsters and in the forestomach of mice. Clinical studies have demonstrated that N-4-(carboxyphenyl) retinamide is effective against oral leukoplakia, vulvar leukoplakia, and dysplasia of the uterine cervix and stomach. Field studies among a population at high risk for esophageal cancer in Linxian County, Henan Province, revealed that N-4-(ethoxycarbophenyl) retinamide decreased the incidence of this cancer. Qidong County is a high-risk area for hepatoma in China. This has been correlated to the low levels of selenium in the blood of the residents as well as in grain grown in the area. S. Y. Yu, W. G. Li, Y. 
J. Zhu, et al. (Biol. Trace Element Res. 1985; 7:22-26) reported that the administration of selenium inhibited the incidence of hepatoma induced by aflatoxin B in rats and in ducks. Experimental studies demonstrated that green tea extract inhibited 12-O-tetradecanoylphorbol-3-acetate-induced epidermal ornithine decarboxylase activity and counteracted 
12-O-tetradecanoylphorbol-3-acetate-induced ear edema in mice. It is interesting that green tea extract inhibited the transformation of Balb/c 3T3 cells induced by methylcholanthrene and 12-O-tetradenanoylphorbol-3-acetate. Garlic has been used for thousands of years in Chinese cooking and folk medicine. Epidemiological studies show that the dietary intake of garlic is inversely related to gastric cancer incidence in Shandong Province. 
PMID: 8234211 [PubMed - indexed for MEDLINE]


26: Carcinogenesis 1991 Feb;12(2):365-7 
Combination of blocking agents and suppressing agents in cancer prevention. 
Ip C, Ganther HE. 
Department of Breast Surgery, Roswell Park Cancer Institute, Buffalo, NY 
14263. 
The design of the present study was based on the premise that if blocking agents and suppressing agents are targeted at different phases of chemical carcinogenesis, a greater chemopreventive effect would be achieved by using the combination treatment compared to the single-agent treatment. The dimethylbenz[a]anthracene (DMBA)-induced mammary tumor model in rats was used to test this hypothesis, with the blocking agent given before DMBA only and the blocking agent given after DMBA until the end of the experiment. A total of three sets of combination treatment were carried out; diallyl sulfide/Se-methylselenocysteine, ellagic acid/selenomethionine, and diallyl sulfide/quercetin. In all three cases, the combination regimen was much more effective than the single-agent treatment in tumor suppression. It should be noted that only naturally occurring inhibitors were selected for these experiments. The impact of minor dietary anutrients in cancer chemoprevention is also discussed. 
PMID: 1899813 [PubMed - indexed for MEDLINE]


27: Mutat Res 1985 Jul;143(3):127-9 
Diallyl sulfide. A naturally occurring thioether that inhibits carcinogen-induced nuclear damage to colon epithelial cells in vivo. Wargovich MJ, Goldberg MT. 
PMID: 4010692 [PubMed - indexed for MEDLINE]


28: Carcinogenesis 2000 Jun;21(6):1149-55 
Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression. 
Wargovich MJ, Jimenez A, McKee K, Steele VE, Velasco M, Woods J, Price R, Gray K, Kelloff GJ. 
Division of Basic Research, South Carolina Cancer Center, Columbia, SC 29203, USA. michael.wargovich@rmh.edu 
We assessed the effects of 78 potential chemopreventive agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol agents were given during the period of AOM administration, whereas in the post-initiation assay the chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The agents were derived from a priority listing based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, 
p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, 
S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis. PMID: 10837003 [PubMed - indexed for MEDLINE] 

29: J Nutr 2001 Mar;131(3s):1010S-5S Antioxidant health effects of aged garlic extract. Borek C. 
Department of Community Health and Family Medicine, Nutrition and Infectious Diseases Unit, Tufts University School of Medicine, Boston, MA 02111, USA. 
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 that are aged over a prolonged period to produce aged garlic extract (AGE) contain antioxidant phytochemicals that prevent oxidant damage. These include unique water-soluble organosulfur compounds, lipid-soluble organosulfur components and flavonoids, notably allixin and selenium. Long-term extraction of garlic (up to 20 mo) ages the extract, creating antioxidant properties by modifying unstable molecules with antioxidant activity, such as allicin, and increasing stable and highly bioavailable water-soluble organosulfur compounds, such as S-allylcysteine and S-allylmercaptocysteine. AGE exerts antioxidant action by scavenging ROS, enhancing the cellular antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and increasing glutathione in the cells. AGE 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. AGE inhibits the activation of the oxidant-induced transcription factor, nuclear factor (NF)-kappa B, which has clinical significance in human immunodeficiency virus gene expression and atherogenesis. AGE protects DNA against free radical--mediated damage and mutations, inhibits multistep carcinogenesis and defends against ionizing radiation and UV-induced damage, including protection against some forms of UV-induced immunosuppression. AGE may have a role in protecting against loss of brain function in aging and possess other antiaging effects, as suggested by its ability to increase cognitive functions, memory and longevity in a senescence-accelerated mouse model. AGE has 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. Substantial experimental evidence shows the ability of AGE to protect against oxidant-induced disease, acute damage from aging, radiation and chemical exposure, and long-term toxic damage. Although additional observations are warranted in humans, compelling evidence supports the beneficial health effects attributed to AGE, i.e., reducing the risk of cardiovascular disease, stroke, cancer and aging, including the oxidant-mediated brain cell damage that is implicated in Alzheimer's disease. 
Publication Types:
Review
Review, tutorial 
PMID: 11238807 [PubMed - indexed for MEDLINE]


30: Microbes Infect 1999 Feb;1(2):125-9 
Antimicrobial properties of allicin from garlic. Ankri S, Mirelman D. Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. 
Allicin, one of the active principles of freshly crushed garlic homogenates, has a variety of antimicrobial activities. Allicin in its pure form was found to exhibit i) antibacterial activity against a wide range of Gram-negative and Gram-positive bacteria, including multidrug-resistant enterotoxicogenic strains of Escherichia coli; ii) antifungal activity, particularly against Candida albicans; iii) antiparasitic activity, including some major human intestinal protozoan parasites such as Entamoeba histolytica and Giardia lamblia; and iv) antiviral activity. The main antimicrobial effect of allicin is due to its chemical reaction with thiol groups of various enzymes, e.g. alcohol dehydrogenase, thioredoxin reductase, and RNA polymerase, which can affect essential metabolism of cysteine proteinase activity involved in the virulence of E. histolytica. 
Publication Types:
Review
Review, tutorial 
PMID: 10594976 [PubMed - indexed for MEDLINE]


31: Planta Med 1999 Mar;65(2):139-43 
Quality of herbal remedies from Allium sativum: differences between alliinase from garlic powder and fresh garlic. Krest I, Keusgen M. Institut fur Pharmazeutische Biologie, Universitat Bonn, Germany. Alliinase (EC 4.4.1.4) has been isolated from commercially available garlic (Allium sativum L., Alliaceae) powder and was investigated with respect to its use as ingredient of herbal remedies. The enzyme was purified to apparent homogeneity and results were compared with those obtained from a sample of fresh 
A. sativum var. pekinense. The purification of the enzyme involved a gel filtration step as well as affinity chromatography on concanavalin-A agarose. Vmax using L-(+)-alliin as substrate (252 mumol min-1 mg-1) was at the lower range of data given in the literature (214-390 mumol min-1 mg-1). L-(-)-Alliin was also accepted as substrate (54 mumol min-1 mg-1). Vmax for alliinase from A. sativum var. pekinense was at 332 mumol min-1 mg-1 and 90 mumol min-1 mg-1 for L-(+)- and L-(-)-alliin, respectively. The Km values for alliinase from garlic powder were estimated to be 1.6 mM for L-(+)-alliin and 2.8 mM for L-(-)-alliin. In contrast to literature values, both temperature and pH optima were somewhat higher (36 degrees C and pH 7.0 versus 33 degrees C and pH 6.5, respectively). The enzyme was found to be active in a range from pH 5 to pH 10. Gel electrophoresis gave evidence that the alliinase obtained from garlic powder consisted of two slightly different subunits with molecular weights of 53 and 54 kDa whereas alliinase obtained from fresh garlic consists of two identical subunits. It is assumed that the alliinase gets significantly altered during the drying process of garlic powder but is still capable to convert alliin to allicin. PMID: 10193205 [PubMed - indexed for MEDLINE] 

32: Med Res Rev 1996 Jan;16(1):111-24 Therapeutic actions of garlic constituents. Agarwal KC. Department of Molecular Pharmacology and Biotechnology, Brown University School of Medicine, Providence, Rhode Island 02912, USA. Most studies on garlic during the past 15 years have been primarily in the fields of cardiovascular and cancer research. Cardiovascular studies have been mainly related to atherosclerosis, where effects were examined on serum cholesterol, LDL, HDL, and triglycerides. Although the studies were not consistent in relation to the dosage, standardization of garlic preparations, and period of treatment, most findings suggest that garlic decreases cholesterol and triglycerides levels in patients with increased levels of these lipids. Lowering of serum lipids by garlic ingestion may decrease the atherosclerosis process. The other major beneficial effect of garlic is due to its antithrombotic actions. This field of garlic research has been extensively studied. Garlic extracts and several garlic constituents demonstrate significant antithrombotic actions both in vitro and in vivo systems. Allicin and adenosine are the most potent antiplatelet constituents of garlic because of their in vitro effects. Since both allicin and adenosine are rapidly metabolized in human blood and other tissues, it is doubtful that these compounds contribute to any antithrombotic actions in the body. In addition, ajoene also seems not to be an active antiplatelet principle, because it is not naturally present in garlic, garlic powders, or other commercial garlic preparations. Only a small amount of ajoene can be found in garlic oil-macerates; however, ajoene is being developed as a drug for treatment of thromboembolic disorders. Recent findings on the identification of potent enzyme inhibiting activities of adenosine deaminase and cyclic AMP phosphodiesterase in garlic extracts are interesting, and may have a significant role in the pharmacological actions in the body. Presence of such enzyme inhibitors in garlic may perhaps explain several clinical effects in the body, including the antithrombotic, vasodilatory, and anticancer actions. Epidemiological studies have suggested that garlic plays a significant role in the reduction of deaths caused by malignant diseases. This had led many investigators to examine garlic and garlic constituents for their antitumor and cytotoxic actions both in vitro and in laboratory animals. The data from these investigations suggest that garlic contains several potentially important agents that possess antitumor and anticarcinogenic properties. In summary, the epidemiological, clinical, and laboratory data have proved that garlic contains many biologically and pharmacologically important compounds, which are beneficial to human health from cardiovascular, neoplastic, and several other diseases. Numerous studies are in progress all over the world to develop effective and odorless garlic preparations, as well as to isolate the active principles that may be therapeutically useful. Publication Types: Review 
Review, tutorial 
PMID: 8788216 [PubMed - indexed for MEDLINE]


33: Mol Cell Biochem 1995 Jul 19;148(2):183-9 
Antioxidant activity of allicin, an active principle in garlic. Prasad K, Laxdal VA, Yu M, Raney BL. 
Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Canada. 
Garlic has been claimed to be effective against diseases, in the pathophysiology of which oxygen free radicals (OFRs) have been implicated. Effectiveness of garlic could be due to its ability to scavenge OFRs. However, its antioxidant activity is not known. We investigated the ability of allicin (active ingredient of garlic) contained in the commercial preparation Garlicin to scavenge hydroxyl radicals (.OH) using high pressure liquid chromatographic (HPLC) method. .OH was generated by photolysis of H2O2 (1.25-10 mumoles/ml) with ultraviolet light and was trapped with salicylic acid which is hydroxylated to produce .OH adduct products 2,3- and 2,5-dihydroxybenzoic acid (DHBA). H2O2 produced a concentration-dependent .OH as estimated by .OH adduct products 2,3-DHBA and 2,5-DHBA. Allicin equivalent in Garlicin (1.8, 3.6, 7.2, 14.4, 21.6, 28.8 and 36 micrograms) produced concentration-dependent decreases in the formation of 2,3-DHBA and 2,5-DHBA. The inhibition of formation of 2,3-DHBA and 2,5-DHBA with 1.8 micrograms/ml was 32.36% and 43.2% respectively while with 36.0 micrograms/ml the inhibition was approximately 94.0% and 90.0% respectively. The decrease in .OH adduct products was due to scavenging of .OH and not by scavenging of formed .OH adduct products. Allicin prevented the lipid peroxidation of liver homogenate in a concentration-dependent manner. These results suggest that allicin scavenges .OH and Garlicin has antioxidant activity. PMID: 8594422 [PubMed - indexed for MEDLINE] 

34: Pediatr Infect Dis J 1993 Jul;12(7):613-4 Antibacterial activity of garlic and onions: a historical perspective. Farbman KS, Barnett ED, Bolduc GR, Klein JO. Maxwell Finland Laboratory for Infectious Diseases, Boston City Hospital Department of Pediatrics, MA 02118. 
PMID: 8346006 [PubMed - indexed for MEDLINE]

35: Environ Mol Mutagen 1989;13(4):357-65 
Studies on the antimutagenic activities of garlic extract. Knasmuller S, de Martin R, Domjan G, Szakmary A. Institute of Experimental Cancer Research, University of Innsbruck, Austria. 
Experiments with Salmonella tester strains indicated that aqueous garlic extract possesses antimutagenic properties toward ionizing radiation, peroxides, adriamycin, and N-methyl-N'-nitro-nitrosoguanidine. The assumption that radical scavenging garlic constituents, i.e., molecules with sulfur moieties, might be responsible for the inhibitory effect of aqueous extract toward mutagenesis induced by radiation and radiomimetic compounds was confirmed by the results of subsequent experiments; 1) garlic extract attenuated the lethal effects of gamma-rays on repair-deficient E. coli strains; 2) the garlic constituent allicin (thio-2-propene-1-sulfinic acid S-allyl ester) is partly responsible for the reduced radiation-induced mutagenesis in Salmonella typhimurium TA 
102. No such inhibitory effects were detected with alliin (S-allyl-L-cysteine sulfoxide) or cysteine; 3) aqueous garlic extract inhibited hydrogen-peroxide-induced lipid peroxidation. Results obtained in preliminary experiments with Chinese hamster ovary cells suggest that the antimutagenic properties of garlic extract are not restricted to procaryotic cells. 
PMID: 2661224 [PubMed - indexed for MEDLINE]


36: Agents Actions 1988 Aug;25(1-2):182-90 
The pharmacological effects of allicin, a constituent of garlic oil. Mayeux PR, Agrawal KC, Tou JS, King BT, Lippton HL, Hyman AL, Kadowitz PJ, McNamara DB. 
Department of Pharmacology, Tulane Medical School, New Orleans, LA. Garlic has been used in herbal medicine for thousands of years. While garlic oil contains many components and has been widely studied, the pharmacology of pure allicin, a constituent of garlic oil, is not well understood. We report that allicin inhibits human platelet aggregation in vitro without affecting cyclooxygenase or thromboxane synthase activity or cyclic adenosine monophosphate (AMP) levels. Allicin does not alter the activity of vascular prostacyclin synthase. However, it inhibits ionophore A23187-stimulated human neutrophil lysosomal enzyme release. In vivo allicin dilates the mesenteric circulation of the cat independent of prostaglandin release or a beta adrenergic mechanism. PMID: 2847508 [PubMed - indexed for MEDLINE] 3

37: Appl Environ Microbiol 1987 Mar;53(3):615-7 Antifungal activity of ajoene derived from garlic. Yoshida S, Kasuga S, Hayashi N, Ushiroguchi T, Matsuura H, Nakagawa S. The antifungal activity of six fractions derived from garlic was investigated in an in vitro system. Ajoene had the strongest activity in these fractions. The growth of both Aspergillus niger and Candida albicans was inhibited by ajoene at less than 20 micrograms/ml. PMID: 3555334 [PubMed - indexed for MEDLINE] 

38: Med Hypotheses 1983 Nov;12(3):227-37 Allium sativum (garlic)--a natural antibiotic. Adetumbi MA, Lau BH. 
Allium sativum (garlic) has been recognized not only as a spice but also as a substance which exerts a control on microorganisms. Recent publications indicate that garlic extract has broad-spectrum antimicrobial activity against many genera of bacteria and fungi. The active component (allicin) has been isolated and characterized. Because many of the microorganisms susceptible to garlic extract are medically significant, garlic holds a promising position as a broad-spectrum therapeutic agent. Furthermore, garlic plants may also play an important role in the ecological control of pathogenic microorganisms in nature. Publication Types: 
Review 
PMID: 6366484 [PubMed - indexed for MEDLINE]


40: Biomed Pharmacother 1997;51(9):397-403 
In vitro suppression of HIV-1 replication by ajoene [(e)-(z)-4,5,9-trithiadodeca-1,6,11-triene-9 oxide] Walder R, Kalvatchev Z, Garzaro D, Barrios M, Apitz-Castro R. Centro de Microbiologia y Biologia Celular, Instituto Venezolano de Investigaciones Cientifica, Caracas, Venezuela. Studies were performed to establish whether synthetic ajoene exhibited differential inhibitory activity against human immunodeficiency virus (HIV)-1 (IIIB) and to clarify the mechanism of its antiviral effects. Our results demonstrate that ajoene protected acutely infected Molt-4 cells against HIV-1 and blocked further destruction of CD4 T-cells in vitro. Ajoene showed dose-dependent inhibition, with 50% cytotoxic concentration (CTC50%) and 50% effective inhibitory concentration (EIC50%) values of 1.88 microM and about 0.35 microM, respectively, when the test compound was added before or after HIV-1 infection and incubation carried out at 37 degrees C for 4 days. Ajoene proved relatively more active than dextran sulfate in blocking HIV-1 virus-cell attachment. The mode of anti-HIV action of ajoene can be ascribed to the inhibition of early events of viral replication, particularly virus adsorption. 
PMID: 9452790 [PubMed - indexed for MEDLINE]


41: Biosci Biotechnol Biochem 1996 Dec;60(12):2086-8 
Antimutagenic effects of ajoene, an organosulfur compound derived from garlic. 
Ishikawa K, Naganawa R, Yoshida H, Iwata N, Fukuda H, Fujino T, Suzuki 
A. 
Bio Development Division, Nagoya Seiraku Co., Ltd., Japan. The antimutagenic effects of ajoene, which is an organosulfur compound derived from garlic, were investigated by the Ames test. Ajoene inhibited mutagenesis induced by both benzo[a]pyrene (B[a]P) and 4-nitro-1,2-phenylenediamine (NPD) in a dose-dependent manner. In particular, NPD-induced mutagenesis was more effectively suppressed by ajoene than the B[a]P-induced type. Furthermore, the inhibition of mutagenesis by ajoene was more effective for transition-type mutations than for the frame shift type. HPLC analysis of B[a]P metabolism in the presence of the rat liver microsomal fraction (S-9) showed that ajoene dose-dependently inhibited the metabolic activation of B[a]P. This suggests that ajoene affected the metabolic enzymes in the S-9 fraction. PMID: 8988645 [PubMed - indexed for MEDLINE] 

42: Appl Environ Microbiol 1996 Nov;62(11):4238-42 Inhibition of microbial growth by ajoene, a sulfur-containing compound derived from garlic. Naganawa R, Iwata N, Ishikawa K, Fukuda H, Fujino T, Suzuki A. Bio Development Division, Nagoya Seiraku Co., Ltd., Japan. Ajoene, a garlic-derived sulfur-containing compound that prevents platelet aggregation, exhibited broad-spectrum antimicrobial activity. Growth of gram-positive bacteria, such as Bacillus cereus, Bacillus subtilis, Mycobacterium smegmatis, and Streptomyces griseus, was inhibited at 5 micrograms of ajoene per ml. Staphylococcus aureus and Lactobacillus plantarum also were inhibited below 20 micrograms of ajoene per ml. For gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, and Xanthomonas maltophilia, MICs were between 100 and 160 micrograms/ml. Ajoene also inhibited yeast growth at concentrations below 20 micrograms/ml. The microbicidal effect of ajoene on growing cells was observed at slightly higher concentrations than the corresponding MICs. B. cereus and Saccharomyces cerevisiae were killed at 30 micrograms of ajoene per ml after 24 h of cultivation when cultivation was started at 10(5) cells per ml. However, the minimal microbicidal concentrations for resting cells were at 10 to 100 times higher concentrations than the corresponding MICs. The disulfide bond in ajoene appears to be necessary for the antimicrobial activity of ajoene, since reduction by cysteine, which reacts with disulfide bonds, abolished its antimicrobial activity. 
PMID: 8900018 [PubMed - indexed for MEDLINE]


43: Biochim Biophys Acta 1989 Nov 6;1006(1):137-9 
Ajoene prevents fat digestion by human gastric lipase in vitro. Gargouri Y, Moreau H, Jain MK, de Haas GH, Verger R. Centre de Biochimie et de Biologie Moleculaire du CNRS, Marseille, France. Human gastric lipase (HGL) is a sulfhydryl enzyme which has been shown by Gargouri et al. (Gargouri, Y., Moreau, H., Pieroni, G. and Verger, R. 
(1988) J. Biol. Chem. 263, 2159-2162) to be inhibited by hydrophobic disulfides. Since HGL is involved in the digestion and absorption of dietary fats we have investigated in vitro the ability of ajoene, a natural disulfide to inactivate HGL. Ajoene is derived from ethanolic garlic extracts. The finding that ajoene inactivates HGL is consistent with the fact that it is reactive towards sulfhydryl compounds and also corroborates previous reports on the ability of garlic to lower triacylglycerol blood levels. These data may explain the age-old Mediterranean and Oriental belief in the 'blood-thinning' effects of garlic on a molecular and physiological basis. PMID: 2804064 [PubMed - indexed for MEDLINE] 

44: J Nutr Sci Vitaminol (Tokyo) 2001 Feb;47(1):78-83 Various cooking methods and the flavonoid content in onion. Ioku K, Aoyama Y, Tokuno A, Terao J, Nakatani N, Takei Y. Faculty of Education, Osaka Kyoiku University, Kashiwara, Japan. Onion is a major source of flavonoids and is cooked in various ways in the world. The major flavonoids in onion are two quercetin glycosides, quercetin 4'-O-beta-glucoside (Q4'G) and quercetin 3,4'-O-beta-diglucosides (Q3,4'G), which are recognized as bioactive substances that are good for our health. We have investigated the effect of cooking procedures on the content of antioxidants. We selected quercetin conjugates, total phenol compounds, and ascorbic acid to estimate the amount of flavonoid ingestion from onion. We examined the following cooking methods: boiling, frying with oil and butter, and microwave cooking. Various cooking methods do not consider the degradation of quercetin conjugates when cooking onion. Microwave cooking without water better retains flavonoids and ascorbic acid. Frying does not affect flavonoid intake. The boiling of onion leads to about 30% loss of quercetin glycosides, which transfers to the boiling water. At that time, the effect of additives on the quercetin conjugates is different according to the compounds. The hydrolysis of quercetin glycosides for daily cooking might occur with the addition of seasonings such as glutamic acid. Additional ferrous ions accelerated the loss of flavonoids. PMID: 11349895 [PubMed - in process] 

45: Nutr Cancer 2000;38(1):116-22 Flavonoids suppress androgen-independent human prostate tumor proliferation. 
Knowles LM, Zigrossi DA, Tauber RA, Hightower C, Milner JA. Graduate Program in Nutrition, Nutrition Department, Pennsylvania State University, University Park, PA 16802, USA. The present studies compared the effects of selected bioflavonoids on the proliferation of androgen-independent human prostatic tumor cells (PC-3). Complete growth retardation was observed in PC-3 cells treated with 100 microM quercetin, kaempferol, and luteolin, while isomolar genistein, apigenin, and myricetin suppressed PC-3 proliferation by 73%, 70%, and 59%, respectively (p < 
0.05). Naringenin and rutin were not as effective and inhibited growth by < 25%. Exposure to increasing concentrations of quercetin and kaempferol led to a dose-dependent decrease in proliferation. Refeeding kaempferol-treated cells (50 microM) complete medium without the flavonoid resulted in a return toward control growth rates. Similar growth recovery was not observed in quercetin-treated cells. The antiproliferative response of PC-3 cells to quercetin and kaempferol was additive when supplemented to the medium at 25 microM. A block in G2-to-M phase progression was observed after the addition of 25 microM kaempferol. When quercetin reached 100 microM, an increase in the proportion of cells in the S phase became apparent within 24 hours. Apoptosis was not evident, even when concentrations of quercetin or kaempferol were raised to 100 microM. The present studies suggest that alterations in cell cycle progression contribute significantly to the antiproliferative effects of quercetin and kaempferol in PC-3 cells. PMID: 11341036 [PubMed - in process] 

46: Br J Pharmacol 2001 May;133(1):117-24 Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats. 
Duarte J, Perez-Palencia R, Vargas F, Ocete MA, Perez-Vizcaino F, Zarzuelo A, Tamargo J. 
Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain. 
1. The effects of an oral daily dose (10 mg kg(-1)) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. 2. Quercetin induced a significant reduction in systolic (-18%), diastolic (-23%) and mean (-21%) arterial blood pressure and heart rate (-12%) in SHR but not in WKY rats. 3. The left ventricular weight index and the kidney weight index in vehicle-treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin-treated SHR in parallel with the reduction in systolic blood pressure. 
4. Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium-dependent relaxation to acetylcholine (E(max)=58+/-5% vs 78+/-5%, P<0.01) in isolated aortae. 5. The 24 h urinary isoprostane F(2 alpha) excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin-treated SHR rats both parameters were similar to those of vehicle-treated WKY. 6. These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug. PMID: 11325801 [PubMed - in process] 

47: Altern Med Rev 2001 Apr;6(2):141-66 Natural therapies for ocular disorders, part two: cataracts and glaucoma. Head KA. 
Thorne Research, Inc., P.O. Box 25, Dover, ID 83825,USA. kathi@thorne.com 
Pathophysiological mechanisms of cataract formation include deficient glutathione levels contributing to a faulty antioxidant defense system within the lens of the eye. Nutrients to increase glutathione levels and activity include lipoic acid, vitamins E and C, and selenium. Cataract patients also tend to be deficient in vitamin A and the carotenes, lutein and zeaxanthin. The B vitamin riboflavin appears to play an essential role as a precursor to flavin adenine dinucleotide (FAD), a co-factor for glutathione reductase activity. Other nutrients and botanicals, which may benefit cataract patients or help prevent cataracts, include pantethine, folic acid, melatonin, and bilberry. Diabetic cataracts are caused by an elevation of polyols within the lens of the eye catalyzed by the enzyme aldose reductase. Flavonoids, particularly quercetin and its derivatives, are potent inhibitors of aldose reductase. Glaucoma is characterized by increased intraocular pressure (IOP) in some but not all cases. Some patients with glaucoma have normal IOP but poor circulation, resulting in damage to the optic nerve. Faulty glycosaminoglycan (GAG) synthesis or breakdown in the trabecular meshwork associated with aqueous outflow has also been implicated. Similar to patients with cataracts, those with glaucoma typically have compromised antioxidant defense systems as well. Nutrients that can impact GAGs such as vitamin C and glucosamine sulfate may hold promise for glaucoma treatment. Vitamin C in high doses has been found to lower IOP via its osmotic effect. Other nutrients holding some potential benefit for glaucoma include lipoic acid, vitamin B12, magnesium, and melatonin. Botanicals may offer some therapeutic potential. Ginkgo biloba increases circulation to the optic nerve; forskolin (an extract from Coleus forskohlii) has been used successfully as a topical agent to lower IOP; and intramuscular injections of Salvia miltiorrhiza have shown benefit in improving visual acuity and peripheral vision in people with glaucoma. Publication Types: Review 
Review, tutorial 
PMID: 11302779 [PubMed - indexed for MEDLINE]


48: Br J Nutr 2000 Dec;84(6):919-25 
Effect of dietary quercetin on oxidative DNA damage in healthy human subjects. 
Beatty ER, O'Reilly JD, England TG, McAnlis GT, Young IS, Geissler CA, Sanders TA, Wiseman H. 
Nutrition, Food & Health Research Centre, Department of Nutrition and Dietetics, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 8WA, UK. 
The effect of dietary intake of flavonols (predominantly quercetin) on oxidative DNA damage was studied in thirty-six healthy human subjects (sixteen men, twenty women). The study was a randomised crossover study, comprising two 14 d treatments of either a low-flavonol (LF) or high-flavonol (HF) diet with a 14 d wash-out period between treatments. Subjects were asked to avoid foods containing flavonols, flavones and flavanols during the LF dietary treatment period and to consume one 150 g onion (Allium cepa) cake (containing 89.7 mg quercetin) and one 300 ml cup of black tea (containing 1.4 mg quercetin) daily during the HF dietary treatment. A 7 d food diary was kept during each dietary period and blood samples were taken after each dietary treatment. Products of oxidative damage to DNA bases were measured in DNA from leucocytes. The study had more than 95% power to detect a change of 20% in DNA damage products Plasma vitamin C and plasma quercetin concentrations were also measured. No significant differences in intake of macronutrients or assessed micronutrients, measured DNA base damage products, or plasma vitamin C were found between the HF and LF dietary treatments. The plasma quercetin concentration was significantly higher after the HF dietary treatment period (228.5 (SEM 34.7) nmol/l) than after the LF dietary treatment period (less than the limit of detection, i.e. <66.2 nmol/l). These findings do not support the hypothesis that dietary quercetin intake substantially affects oxidative DNA damage in leucocytes.
Publication Types:
Clinical trial
Randomized controlled trial 
PMID: 11177210 [PubMed - indexed for MEDLINE]


49: J Hepatol 2000 Nov;33(5):742-50 
The flavonoid quercetin ameliorates liver damage in rats with biliary obstruction. 
Peres W, Tunon MJ, Collado PS, Herrmann S, Marroni N, Gonzalez-Gallego 
J. 
Department of Physiology, University of Leon, Spain. BACKGROUND/AIMS: Our aim was to investigate whether the antioxidant quercetin might protect against liver injury in chronically biliary obstructed rats. METHODS: Secondary biliary cirrhosis was induced by 28 days of bile duct obstruction. Animals received quercetin at 75, 150 and 300 micromol x kg body wt(-1) x day(-1) i.p. through the experimental period or at 150 micromol x kg body wt(-1) x day(-1) i.p. for the last 2 weeks. RESULTS: Bile duct obstruction resulted in a decrease in the activities of antioxidant enzymes. Liver oxidised/reduced (GSSG/GSH) glutathione ratio, hepatic and mitochondrial thiobarbituric acid reactive substances (TBARS) and collagen content were significantly increased and a marked fibrosis and bile ductular proliferation was observed. Quercetin corrected the reduction in glutathione concentration and partially prevented the increase in collagen concentration, TBARS and GSSG/GSH ratio. Treatment resulted in a significant preservation of the activities of antioxidant enzymes, a less pronounced fibrosis and a marked inhibition of bile ductular proliferation. Maximal effects were reached with the intermediate quercetin dose given for 2 or 4 weeks. CONCLUSIONS: Quercetin reduces liver oxidative damage, ductular proliferation and fibrosis in biliary-obstructed rats. These effects suggest that it might be a useful agent to preserve liver function in patients with biliary obstruction. 
PMID: 11097482 [PubMed - indexed for MEDLINE]


50: J Steroid Biochem Mol Biol 2000 Jul-Aug;73(5):265-70 
Quercetin and resveratrol potently reduce estrogen sulfotransferase activity in normal human mammary epithelial cells. Otake Y, Nolan AL, Walle UK, Walle T. 
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, P.O. Box 250505, Charleston, SC 29425, USA. Estrogen sulfotransferase (EST) is the sole sulfotransferase expressed in normal human breast epithelial cells and has an important function in determining free estrogen hormone levels in these cells. In the present study we examined the inhibitory effect of the dietary polyphenols quercetin and resveratrol on EST activity, i.e. 17beta-estradiol (E2) sulfation. Both the compounds potently inhibited recombinant human EST in a competitive fashion with K(i) values of about 1 microM. In fact, both polyphenols could serve as substrates for EST. In order to extend the studies to more physiologically relevant conditions, we examined whether inhibition of EST also occurred in the intact cultured human mammary epithelial (HME) cells. The mean baseline EST activity (E2 sulfate formation) in the HME cells was 4.4 pmol/h per mg protein. The IC(50) for resveratrol was very similar to that for recombinant EST, i.e. about 1 microM. Surprisingly, quercetin was 10 times more potent in the HME cells with an IC(50) of about 0.1 microM, a concentration that should be possible to achieve from the normal dietary content of this flavonoid. PMID: 11070355 [PubMed - indexed for MEDLINE]