Allium sativum (garlic) treatment for murine transitional cell carcinoma.
Cancer (UNITED STATES) May 15 1997, 79 (10) p1987-94
BACKGROUND: Currently, immunotherapy with Bacillus Calmette-Guerin (BCG) is the most effective treatment for superficial bladder carcinoma, but treatment-related toxicity may limit its use in some patients. Alternative treatments are needed for patients who fail to respond to BCG immunotherapy. Allium sativum (AS), or garlic, is known to have a broad range of biologic activities, including immune stimulation and reported antitumor activity. For these reasons, the authors conducted a series of experiments designed to explore the possible therapeutic effects of AS in the MBT2 murine bladder carcinoma model. METHODS: C3H/HeN mice were randomized prior to initiation of each experimental protocol. Mice received 1 x 10(3) MBT2 cells in 0.1 mL RPMI-1640, administered subcutaneously into the right thigh, on Day 0 of the experiment. AS was injected at the site of tumor transplantation on Day 1 and at 2- to 7-day intervals up to Day 28. To evaluate the effects of oral AS in this model, treatment was initiated 30 days prior to tumor inoculation and continued for 30 days after tumor inoculation. Animals in all experiments were followed for tumor incidence, tumor growth, and survival. RESULTS: In the initial experiments, subcutaneous AS significantly reduced tumor volume compared with the saline control (P < 0.05). Unfortunately, treatment-related death was also observed, requiring reduction in the total dose of AS. Animals that received 5 weekly immunizations of AS (5 mg, 5 mg, 1 mg, 1 mg, and 1 mg; cumulative dose = 13 mg) had significantly reduced tumor incidence, tumor growth, and increased survival when compared with animals that received the saline control. No treatment-related deaths were observed with this treatment schedule. To determine whether systemic AS administration might be effective, orally administered AS was tested at doses of 5 mg, 50 mg, and 500 mg per 100 mL of drinking water. Mice that received 50 mg oral AS had significant reductions in tumor volume (P < 0.05) when compared with animals that received the saline control, and mice that received 500 mg oral AS had significant reductions in both tumor volume and mortality (P < 0.05). CONCLUSIONS: The significant antitumor efficacy of subcutaneous and oral AS warrants further investigation and suggests that AS may provide a new and effective form of therapy for transitional cell carcinoma of the bladder.
Garlic (Allium sativum)--a potent medicinal plant
Fortschr Med (GERMANY) Jul 20 1995, 113 (20-21) p311-5
A good deal of evidence suggests beneficial effects of the regular dietary intake of garlic on mild hypertension and hyperlipidemia. Garlic seems to have anti-microbial and immunostimulating properties, enhance fibrinolytic activity, and exert favorable effects on platelet aggregation and adhesion. Standardised preparations guarantee exact dosing and minimize the problem of the strong odour of raw garlic. Thus, a traditional folk remedy has established its usefulness for many patients with less severe forms of cardiovascular disease as a medical drug with very few side effects. The available evidence gives rise to the hope that the list of indications may even be considerably extended in the future. (43 Refs.)
A meta-analysis of the effect of garlic on blood pressure
J Hypertens (ENGLAND) Apr 1994, 12 (4) p463-8
OBJECTIVE: To undertake a systematic review, including meta-analysis, of published and unpublished randomized controlled trials of garlic preparations to determine the effect of garlic on blood pressure relative to placebo and other antihypertensive agents. DATA IDENTIFICATION: Studies were identified by a search of Medline and the Alternative Medicine electronic databases, from references listed in primary and review articles, and through direct contact with garlic manufacturers. STUDY SELECTION: Only randomized controlled trials of garlic preparations that were at least 4 weeks in duration were deemed eligible for inclusion in the review. DATA EXTRACTION: Data were extracted from the published reports by the two authors independently, with disagreements resolved by discussion. RESULTS: Eight trials were identified (all using the same dried garlic powder preparation (Kwai) with data from 415 subjects included in the analyses. Only three of the trials were specifically conducted in hypertensive subjects, and many had other methodological shortcomings. Of the seven trials that compared the effect of garlic with that of placebo, three showed a significant reduction in systolic blood pressure (SBP) and four in diastolic blood pressure (DBP). The overall pooled mean difference in the absolute change (from baseline to final measurement) of SBP was greater in the subjects who were treated with garlic then in those treated with placebo. For DBP the corresponding reduction in the garlic-treated subjects was slightly smaller. CONCLUSIONS: The results suggest that this garlic powder preparation may be of some clinical use in subjects with mild hypertension. However, there is still insufficient evidence to recommend it as a routine clinical therapy for the treatment of hypertensive subjects. More-rigorously designed and analysed trials are needed.
Patient preferences for novel therapy: an N-of-1 trial of garlic in the treatment for hypertension.
J Gen Intern Med (UNITED STATES) Nov 1993, 8 (11) p619-21
The authors used the N-of-1 clinical trial methodology to obtain insights about a patient's preference for garlic for the management of his hypertension. The 61-year-old man received garlic, 500 mg by mouth three times a day (3 weeks), or identical placebo (3 weeks) in three treatment pairs. While the patient was taking garlic the mean systolic blood pressure decreased by 2 mm Hg (95% confidence interval 0.4 to 4.7, p < 0.05), and the diastolic blood pressure decreased by 2.4 mm Hg (95% confidence interval 0.4 to 4, p < 0.025). The treatment effect of garlic was small, but the patient believed continuing garlic for the management of his hypertension was justified.
Can garlic lower blood pressure? A pilot study.
Pharmacotherapy (UNITED STATES) Jul-Aug 1993, 13 (4) p406-7
A popular garlic preparation containing 1.3% allicin at a large dose (2400 mg) was evaluated in this open-label study in nine patients with rather severe hypertension (diastolic blood pressure > or = 115 mm Hg). Sitting blood pressure fell 7/16 (+/- 3/2 SD) mm Hg at peak effect approximately 5 hours after the dose, with a significant decrease in diastolic blood pressure (p < 0.05) from 5-14 hours after the dose. No significant side effects were reported. Our results indicate that this garlic preparation can reduce blood pressure. Further controlled studies are needed, particularly with more conventional doses (e.g., < or = 900 mg/day), in patients with mild to moderate hypertension and under placebo-controlled, double-blind conditions.
Hypertension and hyperlipidaemia: garlic helps in mild cases
Br J Clin Pract Symp Suppl (ENGLAND) Aug 1990, 69 p3-6
Forty-seven non-hospitalised patients with mild hypertension took part in a randomised, placebo-controlled, double-blind trial conducted by 11 general practitioners. The patients who were admitted had diastolic blood pressures between 95 and 104 mmHg after a two-week acclimatization phase. The patients then took either a preparation of garlic powder (Kwai) or a placebo of identical appearance for 12 weeks. Blood pressure and plasma lipids were monitored during treatment after four, eight and 12 weeks. Significant differences between the placebo and the drug group were found during the course of therapy. For example, the supine diastolic blood pressure in the group having garlic treatment fell from 102 to 91 mmHg after eight weeks (p less than 0.05) and to 89 mmHg after 12 weeks (p less than 0.01). The serum cholesterol and triglycerides were also significantly reduced after eight and 12 weeks of treatment. In the placebo group, on the other hand, no significant changes occurred.
Antithrombotic activity of garlic: its inhibition of the synthesis of thromboxane-B2 during infusion of arachidonic acid and collagen in rabbits.
Prostaglandins Leukot Essent Fatty Acids (SCOTLAND) Oct 1990, 41 (2) p95-9
Rabbits were given collagen and arachidonic acid intravenously. Blood pressure, platelet counts, plasma thromboxane-B2 (TXB2) and plasma 6-keto-prostaglandin F1 alpha, (6-keto-PGF1 alpha) were determined. Both thrombogenic agents, upon infusion of a lethal dose, caused thrombocytopenia, indicative of in vivo platelet aggregation and hypotension. These changes were associated with an increase in plasma levels of TXB2 and 6-keto-PGF1 alpha measured by radioimmunoassay (RIA). Pretreatment of rabbits with an aqueous extract of garlic (500 mgkg) provided protection from thrombocytopenia and hypotension. Thromboxane-B2 synthesis was significantly reduced in animals pretreated with garlic and then injected with a lethal dose of either collagen or arachidonic acid. The amount of TXB2 synthesized in these animals was not sufficient to induce thrombocytopenia or hypotension. All animals pretreated with garlic were well protected against the effects of collagen or arachidonate infusion, and no apparent symptoms were observed in these animals. These observations indicate that garlic may be beneficial in the prevention of thrombosis.
Garlic (Allium sativum) and onion (Allium cepa): a review of their relationship to cardiovascular disease
Prev Med (UNITED STATES) Sep 1987, 16 (5) p670-85
Garlic and onion have been used for millenia in the traditional medical practice of many cultures to treat cardiovascular and other disorders. Both Allium species, their extracts, and the chemical constituents of these plants have been investigated for possible effects on cardiovascular disease risk factors--both definite (hyperlipidemia, hypertension and hyperglycemia) and suspected (platelet aggregation and blood fibrinolytic activity). Action of these Allium species on blood coagulability is more clearly defined than their effect on the other risk factors. While many of the studies have serious methodological shortcomings, there is some evidence to suggest that use of certain formulations of garlic and/or onion is accompanied by favorable effects on risk factors in normal subjects and in patients with atherosclerotic disease. The possibility of toxicity resulting from acute and chronic ingestion of large amounts of these plants or their extracts is unresolved. Accordingly, further clinical and epidemiological studies are required before the role of these plants in the prevention and control of cardiovascular disorders is understood and can be realized. Additional research in this area is recommended. (116 Refs.)
Bulgarian traditional medicine: a source of ideas for phytopharmacological investigations
J Ethnopharmacol (SWITZERLAND) Feb 1986, 15 (2) p121-32
Some data about the use of medicinal plants in Bulgarian traditional medicine in the Middle Ages and in modern times are presented and the results of 40-year-long experimental-pharmacological investigations on many medicinal plants used in Bulgarian traditional medicine are reviewed. In-depth discussion is presented on the investigations of garlic (Allium sativum L.), a plant widely used by Bulgarian people for treating different diseases. Data from studies on a large number of plants used for treatment of hypertension, infectious diseases and as diuretic and spasmolytic remedies are summarized. (51 Refs.)
Garlic as a natural agent for the treatment of hypertension: a preliminary report
Cytobios (ENGLAND) 1982, 34 (135-36) p145-52
The major objective of this study was to re-evaluate the effects of garlic on blood pressure with respect to its ability to provoke a decrease in blood pressure and to determine the length of time that this decrease would require. Spontaneously hypertensive rats were given three doses of garlic extract (0.1 ml/kg, 0.25 ml/kg, and 0.5 ml/kg) by oral injection. The blood pressures of these ether-anaesthetized rats were measured immediately before the extract was given, and then 0.5, 2, 4, 6, and 24 h after the extract was given. A blood pressure measurement was also taken at 48 h after extract administration for the 0.5 ml/kg dose. The Gilson Duograph System was used to measure blood pressure by the tail-cuff method. There was a marked decrease in the systolic blood pressure of all of the rats after three doses and the decrease occurred within 30 min in each case. Even though the average decreases for the 0.1 ml/kg and the 0.25 ml/kg doses were calculated as 51,25 mm Hg and 56.25 mm Hg, respectively, these doses were not sufficient to sustain the blood pressure in a normal range for more than 1 or 2 h. The 0.5 ml/kg dose, showing an average decrease of 65.7 mm Hg, was sufficient to provoke a decrease to a normal level and to sustain this decrease for up to 24 h. The results indicate that garlic is effective as a natural agent for the treatment of hypertension.
Plants and hypotensive, antiatheromatous and coronarodilatating action.
Am J Chin Med (UNITED STATES) Autumn 1979, 7 (3) p197-236
However great the success in the therapy of hypertension, atherosclerosis and ischemic heart disease has been gained today by recent efficient drugs, the definite healing of patients is not yet attained. The late discovery of reserpine, such an efficient drug of plant origin against hypertension, convinced so far reluctant scientists to consider the chemical compounds of the plant world. With respect to this traditional medical knowledge, it seems necessary to define more accurately the specificity of these healings-sometimes recommended unspecifically for a whole branch of medicine. This experimental verification should not use inconsiderately the present-day classification of diseases; there should be an awareness that conventional experimental methods in pharmacology are often unsuitable for revealing the real biological activity of one or another medicinal plant. The interest in the millennial empirical field of health care is acknowledged by the World Health Organization which promotes research and development of traditional medicine, along with investigations into its psychosocial and ethnographic aspects. These studies cover a number of plants growing in Bulgaria that have a healing effect in hypertension, atherosclerosis and ischemic heart disease according to the data of traditional medicine. Using screening methods, extracts and chemically pure substances were investigated; extraction was done with solvents such as water, ether, chloroform, dichloretan, ethanol, methanol, and acetone. Most of the experiments were carried out on anesthetized cats, rabbits and dogs. The substances tested were applied mainly intravenously, and in some experiments orally. Chronic experiments were also carried out on wakeful dogs with induced hypertension, on animals fed on an atherogenic diet, and on animals with induced arrhythmia and coronary spasm. Data are presented of clinical examination of some plants or of active substances isolated from them. Major results of these studies are presented for the following plants: Garlic, Geranium; Hellebore; Mistletoe; Olive; Valerian; Hawthorn; Pseucedanum arenarium; Periwinkle; Fumitory. For another 50 plants growing in Bulgaria and in other countries the author presents his and other investigators' experimental and clinical data about hypotensive, antiatheromatous and coronarodilatating action.
Recent advances in the chemotherapy of herpes virus infections
REV. ROUM. MED. (RUMANIA), 1981, 32/1 (57-77)
The main categories of antiherpes agents presently used in chemotherapy are reviewed according to the phase of virus replication affected: 1) virus adsorption (adamantane, nonionic surfactants); 2) eclipse (interferon); 3) virion maturation (nucleoside and nucleotide analogues and phosphonic acid derivatives). Mention is also made of other compounds - different synthetic organic derivatives, photodynamic dyes, metal ions, boric acid, hormones, antibiotics, other natural products (extracts from marine algae, propolis, garlic) - with promising antiviral properties. The difficulties and prospects of viral chemotherapy research are briefly discussed.
Beneficial effects of Allium sativum (garlic), Allium cepa and Commiphora mukul on experimental hyperlipidemia and atherosclerosis--a comparative evaluation.
J Postgrad Med (INDIA) Jul 1991, 37 (3) p132-5
Oral administration of petroleum ether extract of Allium sativum, Allium cepa and ethylacetate extract of Commiphora mukul in albino rats significantly prevented rise in serum cholesterol and serum triglyceride level, caused by atherogenic diet. All the three agents were also found to confer significant protection against atherogenic diet induced atherosclerosis.
"Garlic: A Review of Its Relationship to Malignant Disease"
Preventive Medicine, May 1990;19(3):346-361
This is an extensive review article on the physiologic aspects of garlic with regards to cancer prevention and treatment. This article lists approximately 30 studies from 1949 through 1986 on garlic and cancer. Epidemiologically garlic and onion consumption is associated with reduced mortality from cancer. Garlic is rich in sulfur compounds and may be important in several detoxification pathways. Garlic has antitumor and cancer inhibition properties. There is presently no data from the National Toxicology Program regarding the toxicity of garlic though in animal models negative health effects at very high doses have been reported. Other documented effects of garlic include antiobiotic and antifungal activity, fibrinolysis and platelet aggregation inhibition. The trace elements selenium and germanium, antioxidants in their own right, are constituents of Japanese garlic. Further studies in humans on garlic and cancer are encouraged. 10,040
"Anticandidal and Anticarcinogenic Potentials For Garlic"
International Clinical Nutrition Review, October 1990;10(4):423-429.
This review states that Kyolic garlic extract enhanced the elimination of candida albicans in infected animals. Kyolic can inhibit aflatoxin or benzopyrene induced mutagenesis. It can also inhibit aflatoxin from binding to DNA. Garlic reduces the formation of organosoluble metabolites and increases the formation of water soluble metabolites facilitating elimination of the carcinogen.
S-allylmercaptocysteine inhibits cell proliferation and reduces the viability of erythroleukemia, breast, and prostate cancer cell lines
Nutrition and Cancer (USA), 1997, 27/2 (186-191)
Organosulfur compounds are the biologically active components of allium vegetables. Many health benefits have been ascribed to them, including inhibition of carcinogenesis. Inasmuch as several of these thioallyl compounds arare rapidly inactivated in the body, we have investigated one of the stable components present in aged garlic extract, S-allylmercaptocysteine (SAMC), in an effort to determine whether it can inhibit proliferation of cancer cells. Proliferation and viability of two erythroleukemia cell lines, HEL and OCIM-1, two hormone-responsive breast and prostate cancer cell lines, MCF-7 and CRL-1740, respectively, and normal human umbilical vein endothelial cells in response to different concentrations of SAMC were studied for up to two weeks. There were variations in sensitivity to this organosulfur compound in the different cell lines examined, but the two hormone-responsive cancer cell lines of breast and prostate clearly were far more susceptible to the growth-inhibitory influence of the thioallyl compound. The antiproliferative effect of SAMC was limited to actively growing cells. Human umbilical vein endothelial cells that had reached confluence escaped the reduction in viability so noticeable in the cancer cell lines tested. Our studies thus give evidence of a direct effect of SAMC on established cancer cells.
Prevention of preatheromatous lesions in sand rats by treatment with a nutritional supplement
Arzneimittel-Forschung/Drug Research (Germany), 1996, 46/6 (610-614)
Sand rats fed a hypercholesterolaemic diet containing 0.01% of the anti-thyroid agent 2-mercapto-1-imidazole develop preatheromatous lesions similar to those found in humans, in addition to obesity and insulin resistance. The effects of a nutritional supplement rich in essential fatty acids and garlic extract (Arterodiet (R)) on the appearance and evolution of the lesions were studied. Treatment with this nutritional supplement significantly decreased circulating triglycerides and low-density lipoprotein (LDL)-cholesterol levels but did not alter plasma insulin or glucose levels. Intra-arterial cholesterol levels were also decreased by the treatment which resulted in a normalisation of the atherosclerotic lesions in these animals.
Evaluation of hydroxyl radical-scavenging property of garlic
Molecular and Cellular Biochemistry (USA), 1996, 154/1 (55-63)
Garlic has been reported to provide protection against hypercholesterolemic atherosclerosis and ischemia-reperfusion-induced arrhythmias and infarction. Oxygen free radicals (OFRs) have been implicated as causative factors in these diseases and antioxidants have been shown to be effective against these conditions. The effectiveness of garlic in these disease states could be due to its ability to scavenge OFRs. However, the OFR-scavenging activity of garlic is not known. Also it is not known if its activity is affected by cooking. We therefore investigated, using high pressure liquid chromatography, the ability of garlic extract (heated or unheated) to scavenge exogenously generated hydroxyl radical (.OH). .OH was generated by photolysis of H2O2 (1.2-10 micromoles/ml) with ultraviolet (UV) light and was trapped with salicylic acid (500 nmoles/ml). H2O2 produced .OH in a concentration-dependent manner as estimated by .OH adduct products 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA. Garlic extract (5 - 100 microl/ml) produced an inhibition (30 -100%) of 2,3-DHBA and 2,5-DHBA generated by photolysis of H2O2 (5.00 pmoles/ml) in concentration-dependent manner. Its activity is reduced by 10% approximately when heated to 100degreeC for 20, 40 or 60 min. The extent of reduction in activity was similar for the three heating periods. Garlic extract prevented the .OH-induced formation of malondialdehyde in the rabbit liver homogenate in a concentration-dependent manner. It alone did not affect the MDA levels in the absence of .OH. These results indicate that garlic extract is a powerful scavenger of .OH and that heating reduces its activity slightly.
Therapeutic actions of garlic constituents
Medicinal Research Reviews (USA), 1996, 16/1 (111-124)
Most studies on garlic during the past 15 years have been primarily in the fields of cardiovascular and ctherosclerosis, 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.
Vegetable, fruit, and grain consumption to colorectal adenomatous polyps
American Journal of Epidemiology (USA), 1996, 144/11 (1015-1025)
Previous studies suggest that colorectal cancer risk decreases with higher intake of vegetables, fruits, and grains. Few studies, however, have examined these factors in relation to occurrence of colorectal polyps. The authors used case-control data from 488 matched pairs to evaluate associations of vegetables, fruits, and grains with polyps. Subjects were southern Californians aged 50-74 years who had a sigmoidoscopy in 1991-1993. Diet in the year before sigmoidoscopy was measured with a food frequency questionnaire. Frequent consumption of vegetables, fruits, and grains was associated with decreased polyp prevalence. Specifically, the adjusted odds ratio comparing the highest with the lowest quintile of intake for vegetables was 0.47 (95% confidence interval (CI) 0.29-0.76), for fruits was 0.65 (95% CI 0.40-1.05), and for grains was 0.55 (95% CI 0.33-0.91). The authors also found inverse associations for high carotenoid vegetables, cruciferae, high vitamin C fruits, garlic, and tofu (or soybeans). After further adjusting for potentially anticarcinogenic constituents of these foods, high carotenoid vegetables, cruciferous vegetables, garlic, and tofu (or soybeans) remained inversely associated with polyps. These findings support the hypothesis that high intake of vegetables, fruits, or grains decreases the risk of polyps and suggest that any protective effects might reflect nmeasured constituents in these foods.
Chemoprevention of mammary cancer by diallyl selenide, a novel organoselenium compound
Anticancer Research (Greece), 1996, 16/5 A (2911-2915)
Previous research has demonstrated that structurally distinctive organoselenium compounds are superior to the corresponding sulfur analogs in cancer prevention. The present study was designed to extend this observation to diallyl sulfide (DASe), a volatile synthetic compound, and diallyl sulfide (DAS), a flavor component of garlic. Their anticarcinogenic activities were evaluated using the 7,12-dimethylbenz(a)-anthracene (DMBA)-induced mammary tumor model. Rats were gavaged three times with DASe (6 or 12 micromol/kg body wt) or DAS (300, 900 or 1,800 micromol/kg) at 96, 48, and 24 hours before DMBA treatment. Significant tumor inhibition was found with the two doses of DASe and the highest dose of DAS. Based on these results, DASe appears to be at least 300 times more active than DAS. Analysis ofn the mammary gland and liver showed that DASe had no effect on these parameters, suggesting that DASe might influence some unknown risk-associated events other than carcinogen activation/detoxification. Although the mechanism of action of DASe remains to elucidated, its potential relevance to natural products will be discussed in the context of the chemistry of selenium-enriched garlic which has been reported to be effective in cancer prevention in several studies.
Chemoprotection against the formation colon DNA adducts from the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) in the rat
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis (Netherlands), 1997, 376/1-2 (115-122)
The mutagenic heterocyclic aromatic amine, 2-amino-1-methyl-6-phenylimida zo(4,5-b)pyridine (PhIP), is a pyrolysis product in cooked foods that has been shown to be a rat colon carcinogen and has been implicated in the etiology of human colon cancer. In order to identify chemoprotection strategies that could be carried out in humans, a pilot study was conducted in which PhIP-DNA-adduct levels were quantified in the colons of male F344 rats that had been subjected to 16 different putative chemoprotection regimens, followed by a gavage of PhIP (50 mg/kg) and sacrifice 24 h later. The 16 treatments (Oltipraz, benzylisothiocyanate, diallyl sulfide, garlic powder, ethoxyquin, butylated hydroxyanisole, glutathione, indole-3-carbinol, alpha-angelicalactone, kahweol/cafestol palmitates, quercetin, green tea, black tea, tannic acid, amylase-resistant starch, and physical exercise) comprised sulfur-containing compounds, antioxidants, flavonoids, diterpenes, polyphenols, high dietary fiber, etc. The strangest inhibition of PhIP-DNA adduct formation in the colon was observed upon pretreatment with black tea, benzylisothiocyanate, and a mixture (1:1) of kahweol:cafestol palmitates, which resulted in 67, 66, and 54% decreases in colon PhIP-DNA adduct levels, as compared with controls. Preliminary studies on their mechanism of action indicated that only kahweol:cafestol caused a substantial induction of glutathione S-transferase isozymes (GSTs) that are thought to be important in the detoxification of PhIP. Notably, this induction occurred in the liver rather than in the colon.
Reduction of urinary mutagen excretion in rats fed garlic
Cancer Letters (Ireland), 1997, 114/1-2 (185-186)
Naturally occurring substances of plant origin are known to possess antimutagenic potential. Garlic (Allium sativum) was fed to rats in dried powdered form at 0.1%, 0.5% and 1% concentrations in their diet for 4 weeks. At the end of the experiment benzo(a)pyrene (1 mg/rat) was injected intraperitoneally and 24-h urine was collected from the rats. Urinary mutagens were quantitated by the Salmonella typhimurium assay. There was a significant reduction in the excretion of urinary mutagens by carcinogen-exposed rats fed garlic. Further, there was a stimulation in the activities of liver cytosolic glutathione-S-transferase and liver and lung quinone reductases. The study suggested that the antimutagenic potential of garlic may be mediated through induction of detoxification enzymes in target tissues.
Metabolism of the chemoprotective agent diallyl sulfide to glutathione conjugates in rats
Chemical Research in Toxicology (USA), 1997, 10/3 (318-327)
The chemoprotective effects of diallyl sulfide (DAS), a flavor component of garlic, have been attributed to its inhibitory effects on CYP2E1-mediated bioactivation of certain carcinogenic chemicals. In addition to being a competitive inhibitor of CYP2E1 in vitro, DAS is known to cause irreversible inhibition of CYP2E1 in rats in vivo. The latter property is believed to be mediated by the DAS metabolite diallyl sulfone (DASO2), which is thought to be a mechanism-based inhibitor of CYP2E1, although the underlying mechanism remains unknown. In order to investigate the nature of the reactive intermediate(s) responsible for the inactivation of CYP2E1 by DAS and its immediate metabolites, the present studies were carried out to detect and identify potential glutathione (GSH) conjugates of DAS and its metabolites diallyl sulfoxide (DASO) and DASO2. By means of ionspray LC-MS/MS, ten GSH conjugates were identified in bile collected from rats dosed with DAS, namely: S-(3-(S'-allyl-S'-oxomercapto)-2-hydroxyp ropyl)glutathione (M1, M2; diastereomers), S-(3-(S'-allyl-S'-dioxomercapto) -2-hydroxypropyl)-glutathione (M5), S-(2-(S'-allyl-S'-dioxomercapto)-1-(hydroxymethyl)ethyl)glutathione (M3, M4; diastereomers), S-(3-(S'-allylmercapto)-2-hydroxypropyl)glutathione (M6), S-(3-hydroxypropyl)-glutathione (M7),S-(2-carboxyethyl)glutathione (M8), allyl glutathionyl disulfide (M9), and S-allylglutathione (M10). With the exception of M6, all of the above GSH conjugates were detected in the bile of rats treated with DASO, while only M3, M4, M5, M7, M8, and M10 were found in the bile of rats treated with DASO2. Experiments conducted in vitro showed that GSH reacted spontaneously with DASO to fo, and with DASO2 to form M10. In the presence of NADPH and GSH, incubation of DAS with cDNA-expressed rat CYP2E1 resulted in the formation of metabolites M6, M9, and M10, while incubation with DASO led to the formation of M3, M4, M5, M9, and M10. When DASO2 acted as substrate, CYP2E1 generated only conjugates M3, M4, M5, and M10. These results indicate that while DAS and DASO undergo extensive oxidation in vivo at the sulfur atom, the allylic carbon, and the terminal double bonds, CYP2E1 preferentially catalyzes oxidation of the sulfur atom to form the sulfoxide and the sulfone (DASO and DASO2). However, it appears that the end product of this sequence, namely, DASO2, undergoes further CYP2E1-mediated activation of the olefinic pi- bond, a reaction which transforms many terminal olefins to potent mechanism- based P450 inhibitors. We hypothesize, therefore, that it is this final metabolic event with DASO2 which leads to autocatalytic destruction of CYP2E1 and which is mainly responsible for the chemoprotective effects of DAS in vivo.
Usage and users of natural remedies in a middle-aged population: Demographic and psychosocial characteristics. Results from the Malmo Diet and Cancer Study
Pharmacoepidemiology and Drug Safety (United Kingdom), 1996, 5/5 (303-314)
Background - In Sweden, large amounts of money are spent annually on natural remedies (NRs), in spite of the fact that most products in this category lack scientific documentation of their efficacy and side-effects. The usage and users of natural remedies are not well defined. This paper describes NR use and NR users in a city in southern Sweden, and tests the hypothesis that the use of natural remedies is a strategy for coping with psychosocial stressors. Methods - The study cohort consisted of 6545 men and women, aged 45-65 years, who during 1991 and 1992 participated in the Malmo Diet and Cancer Study, a large-scale prospective cohort study. Data on consumption of natural remedies were recorded during seven consecutive days, as part of a dietary assessment. Each participant also completed a questionnaire, covering education, work history, alcohol and smoking habits, perceived health, and psychosocial factors such as social network, social support, job strain and global control. Body composition was also measured. Results - The prevalence of NR consumption was 26% among women and 17% among men. NR use was most common during winter and spring. The most popular products were ginseng, garlic, and various herb and plant extracts. Important determinants of NR usage were higher education, Swedish origin, and lifestyle factors like low body weight fat percentage and high alcohol consumption among women. Other determinants were higher age and non-smoking among men. None of the psychosocial factors appeared to influence the prevalence of NR consumption. Conclusions - The prevalence of NR consumption is influenced by sex, demographic factors, season of the year, and lifestyle. Use of NRs does not appear to be a common strategy for coping with psychosocial stress.
Effects of S-allyl cysteine sulfoxide isolated from Allium sativum Linn and gugulipid on some enzymes and fecal excretions of bile acids and sterols in cholesterol fed rats
Indian Journal of Experimental Biology (India)), 1995, 33/10 (749-751)
S-allyl cysteine sulfoxide, isolated from garlic, A. sativum, is more or less as active as gugulipid in controlling hypercholesterolemia, obesity and derangement of enzyme activities in cholesterol diet fed rats. The beneficial effects of the drugs are partly due to their inhibitory effects on transaminases, alkaline phosphatase, lipogenic enzymes and HMG CoA reductase and partly due to their stimulatory effects on plasma lecithin-cholesterol acyl transferase lipolytic enzymes and fecal excretion of sterols and bile acids.
Antiperoxide effects of S-allyl cysteine sulphoxide isolated from Allium sativum Linn and gugulipid in cholesterol diet fed rats
Indian Journal of Experimental Biology (India)), 1995, 33/5 (337-341)
Cholesterol containing diet significantly increased not only the body weight, but also the weight of liver and adipose tissue of rats. This is accompanied by a significant increase in blood lipids, atherogenic index and lipid peroxidation and a significant decrease in reduced glutathione level, superoxide dismutase and catalase activities in tissues. Treatment with S-allyl cysteine sulphoxide reverses the deleterious effects of cholesterol diet significantly and almost as effectively as gugulipid.
Potential of food modification in cancer prevention
CANCER RES. (USA), 1994, 54/7 SUPPL. (1957s-1959s)
This presentation focuses on research that could theoretically be applied to implement the strategy of general population chemoprevention. The concept is based on the premise of enhancing foods with known anticarcinogens through either agricultural methods or food-processing technologies. Two areas of our work are described: (a) garlic cultivated with selenium fertilization and (b) foods high in conjugated linoleic acid. Both selenium and conjugated linoleic acid are powerful chemopreventive agents in the animal tumor model. The rationale of delivering these two specific compounds through the food system will be developed. Preliminary studies will be su carcinogen-induced mammary cancer in rats. Finally, the advantages of using foods to provide anticarcinogens to the general population as part of a chemopreventive strategy will also be discussed.
Novel anti-carcinogenic activity of an organosulfide from garlic: Inhibition of H-ras oncogene transformed tumor growth in vivo by diallyl disulfide is associated with inhibition of p21(H-ras) processing
Biochemical and Biophysical Research Communications (USA), 1996, 225/2 (660-665)
In this study, we report a novel anticarcinogenic activity of an organosulfur compound from garlic, diallyl disulfide (DADS). DADS treatment significantly inhibited the growth of H-ras oncogene transformed tumors in nude mice. As compared to controls, the appearance of tumors was also delayed markedly by oral administration of DADS. The inhibition of tumor growth by DADS treatment correlated with the inhibition of p21(H-ras) membrane association in the tumor tissue. The levels of membrane associated p21(H-ras) were mar as compared to controls. An opposite trend, however, was evident for cytosolic p21(H-ras). Furthermore, DADS treatment resulted in a significant inhibition of hepatic as well as tumoral 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. These results indicate that DADS suppresses the growth of H-ras oncogene transformed tumors in nude mice by inhibiting the membrane association of tumoral p21(H-ras).
Organosulfur compounds and cancer
Advances in Experimental Medicine and Biology (USA), 1996, 401/- (147-154)
There is evidence that organosulfur compounds can inhibit the induction and growth of cancer. Several organosulfur compounds are dietary constituents and Allium species are a rich source of such molecules. Some but not all epidemiological studies have suggested that consumption of garlic can decrease cancer incidence. There is substantial evidence that constituents of garlic including diallyl sulfides can inhibit the induction of cancer in experimental animals. Effects on both tumor initiation and promotion have been documented. Some effects may be mediated by modulation of carcinogen metabolism involving altered ratios of phase I and phase II drug metabolizing enzymes. Inhibitory actions on the growth of tumor cells have been documented and, for some tumor cells, differentiating effects of diallyl sulfides can occur. A definitive mechanism of action has not been established and evidence exists for effects at several sites in carcinogen metabolism and regulation of tumor growth. It is not always clear that laboratory studies can be extrapolated to reasonable levels of consumption by humans of garlic or other Allium species.
Modulation of rat hepatic cytochrome P-450 activity by garlic organosulfur compounds
Nutrition and Cancer (USA), 1996, 25/3 (241-248)
Garlic organosulfur compounds exert chemopreventive effects at several organ sites in rodents after administration of chemical carcinogens, possibly by inhibiting carcinogen activation via cytochrome P-450-mediated oxidative metabolism. It has been suggested that the variability in potency of tumor inhibition by garlic sulfur compounds is due to structural differences, such as the number of allyl and sulfur groups. In this study, diallyl sulfide (DAS), diallyl disulfide (DADS), and allyl methyl sulfide (AMS) were administered to acetone-treated adult male Sprague-Dawley rats by gastric gavage at a dose of 1.75 mmol/kg in cottonseed oil. After 15 hours, hepatic microsomal cytochrome P-450 activity and content were examined. The activity of p-nitrophenol (pNP) hydroxylase (E.C 188.8.131.52) was significantly decreased by all garlic compounds, whereas benzphetamine N-demethylase and ethoxyresorufin O-deethylase activities were not changed. The activity of pNP hydroxylase was decreased to 31%, 54%, and 65% of control activity, and immunodetectable CYP2E1 protein levels were decreased in a similar manner by DAS, DADS, and AMS, respectively. Additional acetone-treated rats were given 4-methyl pyrazole, a ligand specific for CYP2E1, intraperitoneally five hours after garlic compound administration. Ten hours later, pNP hydroxylase activity was decreased to 73%, 78%, and 67% of control levels by DAS, DADS, and AMS, respectively. Further studies are needed to determine whether the variable potency of inhibition of CYP2E1 enzyme activity is related to chemopreventive efficacy of garlic sulfur compounds.
Effects of garlic on serum contents of Tch, LDL and HDL observed in MNNG-induced experimental gastric carcinoma and precancerous lesion
Chinese Journal of Clinical Oncology (China), 1996, 23/2 (130-133)
Effect of garlic on level of serum total cholesterol (Tch) low density lipoprotein (LDL) and high density lipoprotein (HDL) in Wistar rats bearing gastric carcinoma and precancerous lesion induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was studied. The results showed that rats of MNNG group (MG) showed lower levels than those of normal control group (NG) in terms of serum HDL, and that the difference was significant, a fact which indicated that experimental gastric carcinomayper-HDL- emia. Comparison between the prevention group (PG) and treatment group (TG) with NG, there was no significant difference. Rats of PG and TG were higher than MG in levels of serum Tch and LDL, the difference between PG and MG groups (P < 0.01), but not between PG and MG groups. This suggested that garlic has inhibitory and reverse effect on MNNG-induced experimental gastric carcinoma and precancerous lesion.
Garlic and associated allyl sulfur components inhibit N-methyl-N-nitrosourea induced rat mammary carcinogenesis
State University, Un02/1-2 (199-204)
Our previous studies demonstrated that dietary garlic powder supplementation inhibits N-nitrosamine induced DNA alkylation in liver and mammary tissue. The present studies compared the impact of dietary supplementation with garlic powder or two garlic constituents, water-soluble S-allyl cysteine (SAC) and oil-soluble diallyl disulfide (DADS), on the incidence of mammary tumorigenesis induced by N-methyl-N-nitrosourea (MNU). Female Sprague-Dawley rats were fed semi-purified casein based diets with or without supplements of garlic powder (20 g/kg), SAC (57 micromol/kg) or DADS (57 micromol/kg) for 2 weeks prior to treatment with MNU (15 mg/kg body wt). Garlic powder, SAC and DADS supplementation significantly delayed the onset of mammary tumors compared to rats receiving the unsupplemented diet. Tumor incidence 23 weeks after MNU treatment was reduced by 76, 41 and 53% in rats fed garlic, SAC and DADS, respectively, compared to controls (P < 0.05). Total tumor number was reduced 81, 35 and 65% by these supplements, respectively (P < 0.05). In a separate study the quantity of mammary DNA alkylation occurring 3 h after MNU treatment was reduced in rats fed garlic, SAC or DADS (P < 0.05). Specifically, O6-methylguanine adducts were reduced by 27, 18 and 23% in rats fed supplemental garlic, SAC and DADS, respectively, compared to controls. N7-Methylguanine adducts decreased by 48, 22 and 21% respectively, compared to rats fed the control diet. These studies demonstrate that garlic and associated allyl sulfur components, SAC and DADS, are effective inhibitors of MNU-induced mammary carcinogenesis.