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Supplement: Recent Advances on the Nutritional Effects Associated with the Use of Garlic as a Supplement

Cholesterol-Lowering Effect of Garlic Extracts and Organosulfur Compounds: Human and Animal Studies¹

Department of Nutrition, The Pennsylvania State University, University Park, PA 16802

²To whom correspondence should be addressed. E-mail: yyy1{at}psu.edu.

ABSTRACT

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 -glutamyl-S-allylcysteine (GSAC), -glutamyl-S-methylcysteine (GSMC) and -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.

KEY WORDS: • garlic • organosulfur compounds • cholesterol • triacylglycerol • hepatocyte

Medicinal use of garlic (Allium sativum) has existed for centuries (Dausch 1990 , Han 1993 ), but there was little scientific support of its therapeutic and pharmacologic properties until recently. Epidemiologic studies in the past 10 years have revealed an inverse relationship between garlic consumption and the incidence of certain forms of cancer, including stomach, colon and laryngeal cancers (Buiatti et al. 1991 , Mei et al. 1989 , Steinmetz et al. 1994 , Sumiyoshi and Wargovich 1990 , Zheng et al. 1992 ). Animal studies have further substantiated the cancer-protective properties of garlic and various garlic preparations. Studies have shown that garlic extract and its constituents were effective in reducing the incidence of chemically induced mouse colon tumors (Sumiyoshi and Wargovich 1990 ) and rat mammary tumors (Amagase and Milner 1993 , Lin et al. 1994 , Liu et al. 1992 , Schaffer et al. 1996 ). Organosulfur compounds of garlic also inhibited the growth of the human tumor cell lines HCT-15 (colon), SK MEL-2 (skin) and A549 (lung) in vitro (Sakamoto et al. 1997 , Sundaram and Milner 1996 ). In addition, garlic has been shown to possess antithrombotic (Srivastava and Tyagi 1993 ), antiplatelet aggregation and antioxidative properties (Kiesewetter et al. 1993 , Sendl et al. 1992 , Yamasaki et al. 1994 ), and to stimulate the phagocytotic function of macrophage and lymphocyte proliferation (Tadi et al. 1990 ).

The cardiovascular-protective effects of garlic have also been evaluated extensively in recent years. In animal experiments, garlic extracts have been shown to lower plasma lipid and cholesterol in rats (Chang and Johnson 1980 , Chi 1982 , Itokawa et al. 1973 , Mathew et al. 1996, Yeh and Yeh 1994 ), rabbits (Bordia et al. 1975 , Bordia and Verma 1980 ), chickens (Qureshi et al. 1983a , Qureshi et al. 1983b ) and swine (Qureshi et al. 1987 ). Moreover, a number of intervention studies have similarly shown that garlic and garlic preparations significantly reduced plasma lipids, especially total cholesterol and LDL cholesterol in humans (Arora and Arora 1981 , Bordia 1981 , Jain et al. 1993 , Lau et al. 1987 , Steiner et al. 1996 , Yeh et al. 1997 , Zimmerman and Zimmerman 1990 ). Aside from the reported antiplatelet aggregation and antithrombotic action, garlic reduced blood pressure (Ernst 1987 , Silagy and Neil 1994a , Steiner et al. 1996 ) and stimulated fibrinolytic activity (Arora et al. 1981 , Ernst 1987 ). Two meta-analyses of randomized, placebo-controlled human studies confirmed the hypocholesterolemic effects of garlic (Silagy and Neil 1994b , Warshafsky et al. 1993 ). The analyses further detected that the extent of the cholesterol-lowering properties of garlic differed markedly from one study to another (Silagy and Neil 1994b , Warshafsky et al. 1993 ). It was estimated from the five randomized clinical trials that hypercholesterolemic patients treated with garlic had a mean plasma cholesterol concentration that was 9% lower than that of patients treated with placebo (Warshafsky et al. 1993 ). Silagy and Neil (1994b) , on the other hand, concluded from the analysis of 17 human studies that plasma cholesterol concentrations of the subjects treated with garlic were 12% lower than those receiving placebo. Furthermore, the two analyses detected a wide range of decrease in mean plasma cholesterol concentrations (i.e., 6–53 mg/dL) among the studies. However, garlic supplementation has been shown not to decrease plasma cholesterol concentrations in human studies by Simons et al. (1995) , Berthold et al. (1998) and Isaacsohn et al. (1998) . Although the reasons for the inconsistent observations are not readily apparent, it is worthwhile to note that garlic contains a variety of organosulfur compounds, amino acids, vitamins and minerals (Block 1985 ). Some of the sulfur compounds such as allicin, ajoene, S-allylycysteine (SAC),³ diallyl disulfide (DADS), S-methylcysteine sulfoxide, and S-allylcysteine sulfoxide may be responsible for the therapeutic properties of garlic (Chi et al. 1982 ). Despite the fact that the mechanisims primarily responsible for the hypocholesterolemic action of garlic are uncertain at present, the composition and quantity of the sulfur components of different garlic preparations used in various studies could account in part for the inconsistent findings. Other contributing factors may include the subject recruitment, duration of experiment, dietary control, lifestyle and methods of lipid analyses (Silagy and Neil 1994b , Warshafsky et al. 1993 ).

The mechanism by which garlic or garlic preparations reduce plasma lipids has not been fully investigated. Animal studies, however, have shown that garlic supplementation in the diet depressed the hepatic activities of lipogenic and cholesterogenic enzymes such as malic enzyme, fatty acid synthase, glucose-6 phosphate dehydrogenase (Chi 1982 , Chi et al. 1982 , Qureshi et al. 1983a ) and 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (Qureshi et al. 1983a, 1983b and 1987 ). It is, therefore, reasonable that the hypocholesterolemic effect of garlic may stem in part from impaired cholesterol synthesis. In fact, we observed recently that garlic extracts that contained various sulfur compounds effectively decreased the plasma concentration of cholesterol, resulting possibly from an inhibition of hepatic cholesterol synthesis (Yeh and Yeh 1994 ).

The objectives of this article were to review the data on the cholesterol-lowering properties of garlic extracts in humans and animals and to summarize in vitro studies aimed at identifying the active sulfur compounds of garlic responsible for inhibition of cholesterol synthesis observed in our laboratories (Liu and Yeh 2000 , Yeh and Yeh 1994 , Yeh et al. 1997 ).

Human studies.

In view of the potential confounding variables mentioned above, we designed a double-blind, randomized, placebo-controlled intervention study of free-living hypercholesterolemic subjects. Men (n = 34; 48.2 ± 0.8 y old) with plasma cholesterol concentration between 220 and 285 mg/dL were recruited into the study. The detailed account of the subjects and experimental design were described previously (Yeh et al. 1997 ). Briefly, the subjects were divided randomly into two groups (n = 17/group) to receive either garlic extract or placebo as dietary supplement for 5 mo. The subjects were asked to adhere strictly to their normal food habits and maintain healthy lifestyles. Each subject of the garlic group consumed daily 9 capsules, each containing 800 mg of aged garlic extract (AGE), whereas the placebo subjects took 9 capsules, each containing 800 mg of a common food ingredient. The capsules were prepared and provided by Wakunaga of America (Mission Viejo, CA). Plasma lipids were determined at the baseline period and 2, 4 and 5 mo after treatment. To ensure reliable quantitative measurements of plasma lipids, the regular quality controls of the Centers for Disease Control with known values of total cholesterol, HDL cholesterol and triacylglycerol were used as references in routine assays.

The mean baseline plasma total cholesterol concentrations were 246 ± 5 and 243 ± 5 mg/dL for the garlic and placebo groups, respectively (Yeh et al. 1997 ). Plasma concentrations of all lipids tested remained unchanged 2 mo after the supplementation of either AGE or placebo. Five months after the supplementation of AGE, the mean plasma concentration of total cholesterol was 7% (18 mg/dL) lower than the baseline value (Fig. 1A ). Similarly, AGE supplementation reduced the mean plasma LDL cholesterol concentration by 10% (17 mg/dL) from its baseline level of 162 ± 4 mg/dL during the same time period (Fig. 1B ). Although plasma concentrations of total and LDL cholesterol began to decrease by mo 4 of AGE supplementation, the changes were not significant. In contrast, mean plasma concentrations of total and LDL cholesterol were not altered in the group supplemented with the placebo for as long as 5 mo. At the conclusion of the study, i.e., 5 mo after the supplementation, mean plasma concentrations of total and LDL cholesterol of the AGE-treated group were 17 and 21 mg/dL lower, respectively, than those of the placebo-treated group. Plasma concentrations of HDL cholesterol and triacylglycerol remained constant throughout the study in the subjects regardless of the treatment.

View larger version (25K): [in this window] [in a new window]   Figure 1. Reduction of plasma concentrations of total and LDL cholesterol by aged garlic extract supplementation in hypercholesterolemic men. Panel A shows plasma total cholesterol; panel B represents plasma LDL cholesterol. Closed circles and triangles represent placebo group; open circles and triangles represent the group supplemented with aged garlic extract. Values are means ± SEM, n = 16 or 17. Values without a common superscript are significantly different at P < 0.05.

Animal studies.

The mechanism underlying the hypocholesterolemic action of AGE is not clear from our human study. Previous studies by other investigators have shown that the lipid-lowering effects of various garlic extracts were accompanied by depressed activities of lipogenic and cholesterogenic enzymes (Chi 1982 , Chi et al.1982 , Qureshi et al. 1983a, 1983b and 1987 ). Prompted by these findings, we conducted in vitro experiments using cultured rat hepatocytes to determine whether garlic decreases cholesterol synthesis (Yeh and Yeh 1994 ). Before the in vitro study, an animal feeding experiment was undertaken to confirm the lipid-lowering effect of garlic reported in different animal species (Chang and Johnson 1980 , Chi 1982 , Chi et al. 1982 , Itokawa et al. 1973 , Kamanna and Chandrasekhara 1982 ). Two groups of male Sprague-Dawley rats were fed either an AIN 76-diet containing 20 g/100 g fat, or a similar diet supplemented with 2 g/100 g AGE. Four weeks after the feeding, plasma concentrations of total cholesterol and triacylglycerol of the AGE-supplemented rats were 15 and 30% lower, respectively, than those of the nonsupplemented counterparts (Fig. 2 ). This finding led to subsequent experiments that used cultured rat hepatocytes to evaluate the possible role of garlic in cholesterol biosynthesis.

View larger version (17K): [in this window] [in a new window]   Figure 2. Lipid-lowering effect of aged garlic extract (AGE) in rats. Two groups of rats were fed AIN-76 diet (i.e., control diet, AIN 1977 ) or the same diet supplemented with 2 g/100 g AGE for 4 wk. At the end of the feeding, the fasting plasma cholesterol and triacylglycerol concentrations were determined. Open bars and closed bars represent the control and AGE-supplemented rats, respectively. Values are means ± SEM, n = 5. Values without a common superscript are significantly different at P < 0.05.

View larger version (18K): [in this window] [in a new window]   Figure 3. Inhibition of cholesterol synthesis by aged garlic extracts in cultured rat hepatocytes. Rat hepatocytes were maintained in Dulbecco’s modified Eagle’s medium supplemented with 5.6 mmol/L glucose, 10% fetal bovine serum and antibiotics (100 U penicillin/mL and 100 µg streptomycin/mL). Cells were incubated with the petroleum ether extractable fraction (PEF), methanol extractable fraction (MEF) and water extractable fraction (WEF) of fresh garlic at 1.25 g/L, Kyolic at 0.4 mmol/L and S-allylcysteine (SAC) at 2.0 mmol/L. The rates of [2-14C]acetate incorporation into cholesterol ranged from 121 to 158 pmol acetate/(mg protein · 4 h) for the control group. Values are means ± SEM for three experiments. Values without a common superscript are significantly different at P < 0.05.

Active garlic components and cholesterol synthesis.

The requirement of the concerted action of multiple components of garlic led us to identify the active organosulfur compounds and their potency for inhibition of cholesterol synthesis (Liu and Yeh 2000 ). In this study, cultured rat hepatocytes were used to test the inhibition potency of organosulfur compounds derived from garlic. Included were water-soluble compounds, i.e., SAC, SEC, SPC, S-methylcysteine (SMC), -glutamyl S-allylcysteine (GSAC), -glutamyl S-methylcysteine (GSMC), -glutamyl S-propylcysteine (GSPC), S-allyl acetylcysteine (SAAC), S-allyl sulfonylalanine (SASA), S-allylmercaptocysteine (SAMC) and alliin. Lipid-soluble compounds were diallyl sulfide (DAS), DADS, diallyl trisulfide (DATS), dipropyl sulfide (DPS), dipropyl disulfide (DPDS) and methyl allylsulfide (MAS).

The cells were treated with [2-¹⁴C]acetate in the presence or absence of the test compounds at 0.05–4.0 mmol/L for measurement of cholesterol synthesis. Among water-soluble compounds, S-alk(en)ylcysteines (i.e., SAC, SEC and SPC) exhibited dose-dependent inhibition on the rate of cholesterol synthesis with maximal 40–60% inhibition achieved at 2.0–4.0 mmol/L concentrations. Glutamate derivatives of S-alk(en)ylcysteines (i.e., GSAC, GSMC and GSPC) depressed the synthesis by 20–35%. Alliin, SAAC and SASA had no inhibitory effect. Lipid-soluble DAS, DADS, DATS, DPS and DPDS decreased the rate of cholesterol synthesis by 10–15% at concentrations of 0.05–0.5 mmol/L. At higher concentrations (i.e., 1.0, 2.0 and 4.0 mmol/L), DATS, DADS and DPDS, respectively, diminished the rate of [2-¹⁴C] acetate incorporation into cholesterol. MAS did not affect the rate of cholesterol synthesis. Incubation of hepatocytes with each of the lipid-soluble sulfur compounds caused a dose-dependent increase in secretion of cellular lactate dehydrogenase (LDH) into the culture medium. More than 90% of total cellular LDH was released into the medium in the presence of high concentrations of DATS (1.0 mmol/L), DADS (2.0 mmol/L) and DPDS (4.0 mmol/L), suggesting that these compounds were cytotoxic. The cells incubated without the test compound released 13–16% of the cellular LDH. This level of LDH secretion was unaltered by the water-soluble sulfur compounds except for SAMC. Interestingly, SAMC at high concentrations (i.e., 2.0 and 4.0 mmol/L) also abolished the rate of cholesterol synthesis and was accompanied by 80% secretion of the cellular LDH. These results suggest that the inhibition in cholesterol synthesis by water-soluble sulfur compounds is attributable to an impairment in the cholesterol synthetic pathway, whereas the inhibition by lipid-soluble compounds results from their potent cytotoxicity. However, it should be noted that the inhibition of cholesterol synthesis by a low concentration of DADS has been attributed to suppression of HMG-CoA reductase as well (Gebhardt and Beck 1996 ). Consistent with the present in vitro observation, different garlic preparations supplemented in animal diets were shown to depress hepatic synthesis of cholesterol (Qureshi et al. 1983a, 1983b and 1987 ).

The concentration-dependent inhibition of cholesterol synthesis permitted us to estimate the 50% inhibitory concentration (IC₅₀) for water-soluble compounds. The maximal inhibition of cholesterol synthesis by SAC, SPC, SEC, GSAC and GSPC was 62, 51, 45, 38, 21, and 21%, respectively, and the calculated IC₅₀ was 1.22, 0.34, 1.12, 0.66, 1.75 and 1.88 mol/L, respectively. It should be pointed out that SAC is the major water-soluble sulfur compound of garlic. Although SAC content might vary from one preparation to another, AGE has been reported to contain 456 µg SAC/g powder (Amagase and Milner 1993 ). On the bases of the maximal inhibition, the IC₅₀ and the concentration present in AGE, SAC could be the major sulfur compound responsible for the cholesterol-lowering effect seen in our animal feeding study and human intervention study.

Summary

We have demonstrated the cholesterol-lowering effects of AGE in both humans and rats. Although the mechanism(s) is not completely understood, the data from our animal study indicate that the hypocholesterolemic action of garlic stems in part from inhibition of hepatic cholesterol synthesis. Our in vitro studies further revealed that water-soluble organosulfur compounds, especially SAC, are potent inhibitors of cholesterol synthesis, and hence may be the major principles of garlic responsible for the reduction of plasma cholesterol level.

ACKNOWLEDGMENTS

The authors are thankful for technical expertise provided by Shelley Evans and Shaw-Mei Yeh.

FOOTNOTES

¹ Presented at the conference "Recent Advances on the Nutritional Benefits Accompanying the Use of Garlic as a Supplement" held November 15–17, 1998 in Newport Beach, CA. The conference was supported by educational grants from Pennsylvania State University, Wakunaga of America, Ltd. and the National Cancer Institute. The proceedings of this conference are published as a supplement to The Journal of Nutrition. Guest editors: John Milner, The Pennsylvania State University, University Park, PA and Richard Rivlin, Weill Medical College of Cornell University and Memorial Sloan-Kettering Cancer Center, New York, NY.

³ Abbreviations used: AGE, aged garlic extract; DADS, diallyl disulfide; DAS, diallyl sulfide; DATS, diallyl trisulphide; DPDS, dipropyl disulfide; DPS, dipropyl sulfide; GSAC, -glutamyl-S-allylcysteine; GSMC, -glutamyl-S-methylcysteine; GSPC, -glutamyl-S-propylcysteine; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA; IC₅₀, 50% inhibitory concentration; LDH, lactate dehydrogenase; MAS, methyl allylsulfide; MEF, methanol-extractable fraction; PEF, petroleum ether-extractable fraction; SAAC, S-allyl acetylcysteine; SAC, S-allylcysteine; SAMC, S-allylmercaptocysteine; SASA, S-allyl sulfonylalanine; SEC, S-ethylcysteine; SMC, S-methylcysteine; SPC, S-propylcysteine; VLDL, very low-density lipoprotein; WEF, water-extractable fraction.

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