Chapter 21
Bioactive Organosulfur Compounds of Garlic and Garlic Products Downloaded by NORTH CAROLINA STATE UNIV on December 6, 2012 | http://pubs.acs.org Publication Date: May 5, 1993 | doi: 10.1021/bk-1993-0534.ch021
Role in Reducing Blood Lipids Larry D. Lawson Murdock Healthcare, 10 Mountain Springs Parkway, Springville, UT 84663
Garlic (Allium sativum L.) and some of its derived products have well -established biological activities as antibiotics and as agents in reducing the risk factors of cardiovascular disease, and have received growing support as potential anticancer agents. However, because garlic's organosulfur compound composition varies greatly with the method of processing and because analysis of most of these compounds has only been recently achieved, there has been considerable variation in the experimental conditions, and subsequent results, in the biological studies with garlic and garlic products. This chapter discusses the importance of garlic's organosulfur compounds and the many changes that occur in their chemistry when garlic is crushed, cooked, ingested, metabolized, or commercially processed. The large variation in composition of commercial garlic products necessitates standardization of these products, especially for use in biological studies. Rapid pre -hepatic physiological changes occur to as yet undetected compounds in the blood, thus making in vitro and organ perfusion studies of limited value. The clinical studies on the cardiovascular effects of garlic preparations are summarized, and evidence is presented that low doses of allicin (allyl 2-propenethiosulfinate) and the vinyl-dithiin oils are significant blood lipid-reducing agents.
Garlic (Allium sativum L.) has been considered a valuable healing agent by people of many different cultures for thousands of years. Even today it is commonly used by much of the world, especially in eastern Europe and Asia, for its medicinal benefits. In the modern country of Germany, sales of garlic preparations rank with those of the leading prescription drugs. Garlic is also one of the most researched medicinal plants. Since 1960 (through December 1992) there have been approximately 940 research papers published (1200 in the past 100 years) on the chemistry (260) and biological effects (680) of garlic and its related compounds and preparations. About 75% of
0097-6156/93/0534-0306$07.25A) © 1993 American Chemical Society In Human Medicinal Agents from Plants; Kinghorn, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
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these investigations have been published since 1980. The biological studies since 1960 have focused chiefly on the cardiovascular (234), antimicrobial (126), and anticancer (143) effects of garlic, and, to a lesser extent, on its hypoglycemic (13), heavy-metal poisoning antidote (13), and liver-protective (8) effects. Interest in the therapeutic potential of garlic has produced three recent international symposia on garlic held in Luneburg, Germany in 1989, Washington, D.C. in 1990, and Berlin in 1991. The most extensive review of the biological and chemical studies on garlic up through 1987 was published in German by Koch and Hahn (1). Less extensive reviews on the biological effects of garlic through 1987 have been published by Fenwick and Hanley (2), Hanley and Fenwick (3), Sprecher (4), Reuter (5), Abdullah et al (6), and Petkov (7). Koch has recently reviewed the hormonal actions (8) and metabolism (9) of garlic. Recent reviews on the organosulfur chemistry of garlic and garlic products have been published-by Block (10) and Sticher (11). Other reviews on the chemistry of garlic have been authored by Fenwick and Hanley (12), Block (13,14), Lancaster and Boland (75), Whitaker (16,17), Lutomski (18), and Raghavan et al. (19). Reviews on the effects of garlic on cardiovascular disease (20-25) and cancer (25-25) up to 1990 have also been published. Although garlic has been traditionally eaten as the cooked or chopped clove, it is currently frequently consumed in the form of encapsulated commercial products, particularly when used for health reasons, because of convenience, consistency of dose, and avoidance of garlic odor. In fact, a large percentage of the clinical studies on garlic have employed a processed garlic product. Thus, any discussion of the composition and biological effects of garlic must also include the various commercial products of garlic. Unfortunately, the several forms of processed garlic are frequently called "garlic" in both the lay and scientific literature, even though their composition often differs greatly from whole or crushed garlic cloves, qualitatively and quantitatively, depending on the processing method utilized and the source (29). It is the purpose of this paper to describe the current knowledge of the chemistry, content, and metabolism of the organosulfur compounds from garlic and garlic preparations (which knowledge has improved dramatically in the past four years) and to relate this knowledge to the different types of biological activities, especially the blood lipid-lowering effects, that have been reported for garlic and its preparations. Chemistry and Analysis: Organosulfur Compounds of Garlic and Processed Garlic Reasons for the Interest in Garlic's Organosulfur Compounds. The vast majority of the chemical and biological studies on garlic have focused on its organosulfur compounds because in vitro and animal studies have long shown that removal of thiosulfinates from crushed garlic by solvent (ether) extraction, or inhibition of thiosulfinate formation, also removes the antibacterial (30, 31), antiatherosclerotic (32), blood lipid-lowering (33, 34), and, more recently, the whole-blood platelet aggregation inhibiting (35) effects of garlic. Furthermore, the blood pressure-lowering effect of crushed garlic, which is not removable by solvent extraction (36), also appears to be due to another class of organosulfur compounds in garlic, the yglutamyl-5-alkylcysteines, as indicated by the inhibition of the blood pressure-
In Human Medicinal Agents from Plants; Kinghorn, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
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regulating hormone, angiotensin-converting enzyme (37, 38). Therefore, this review on the bioactive compounds of garlic will deal almost strictly with its organosulfur compounds. Selenium, an element of the same group as sulfur and which can replace the sulfur of organosulfur compounds, has been occasionally cited as an important medicinal component of garlic. However, the selenium content of garlic cloves is extremely low, 0.01-0.2 ng/g fresh wt. (39, 40), compared to the Recommended Dietary Allowance (41) of 70 fig/day (equivalent to 1 kg garlic/day). Nevertheless, the selenium content of garlic has been increased to 50 /*g/g by cultivation in selenium-enriched soil for the purpose of improving the antitumor effects of garlic (40). Germanium has likewise been cited in the lay literature as an important element in garlic, but we have found garlic cloves to contain only 0.004 jig/g of germanium.
Organosulfur Compounds of Whole Garlic Cloves. All of the organosulfur compounds of intact garlic cloves contain the amino acid cysteine (except for trace amounts of methionine), and include approximately equal amounts of the Salkylcysteine sulfoxides (cys-S(O)-R) and 7-glutamyl-S-alkylcysteines (7-glu-cys-S-R), the alkyl groups being strictly allyl, methyl, andtai/tf-l-propenyl(42) (see Table I).
Table I. Principal Organosulfur Compounds in Whole and Crushed Garlic Cloves Compound
Whole Garlic
Crushed Garlic
(mg/g) 5-( -h VAlkvl-L-cvsteine sulfoxides* Allylcysteine sulfoxide (alliin) Methylcysteine sulfoxide fra/w-l-Propenylcysteine sulfoxide (isoalliin)
b
7-14 0.5-2 0.1-2
nd nd nd
3-9 2-6 0.1-0.4
3-9 2-6 0.1-0.4
nd nd nd nd nd
2.5-4.5 0.3-1.2 0.05-1.0 0.02-0.2 0.05-0.15
c
-v-T rG1utamv1-^-alkvl-L-cvsteines 7-Glutamy1-S-rra/w-1 -propenyIcy steine 7-Glutamyl-S-allylcysteine 7-Glutamyl-S-methylcysteine Alkvl alkanethiofnilfinates Allyl 2-propenethiosulfinate (allicin) Allyl methyl thiosulfinates (2 isomers) Allyl froftff-l-propenyl thiosulfinates (2 isomers) Methyl fra/w-l-propenyl thiosulfinates (2 isomers) Methyl methanethiosulfinate a b 0
Determined by calculation from the thiosulfinates (48). Not detectable. Range for 8 varieties of garlic less than 2 months after harvesting.
In Human Medicinal Agents from Plants; Kinghorn, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
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Although it has been known for several decades that garlic contains 5-allyl and Smethyl derivatives of cysteine sulfoxide (43, 44) and 7-glutamylcysteine (45, 46), the presence of the f/wis-l-propenyl homologues was not known until 1990 (47). S-trans1-Propenylcysteine compounds were previously thought to be unique to onions and other non-garlic alliums (12, 15). The presence of S-rra/w-l-propenylcysteine sulfoxide (isoalliin) was first indicated by the discovery of fro/w-l-propenyl thiosulfinates in garlic homogenates (42, 47, 48), followed by its isolation and structure elucidation (49). 7-Glutamyl-5'-rwiy-l-propenylcysteine, the most abundant 7-glutamylcysteine and the second most abundant sulfur compound in garlic, was first found in chive seeds (Allium schoenoprasum L.) by Virtanen (50). It was first discovered and isolated from garlic and its structure determined chemically by Lawson et al. (42, 47). The structure has subsequently been confirmed with spectral data by Mutsch-Eckner et al. (51). The 7-glutamylcysteines, which serve as reserve compounds for the formation of cysteine sulfoxides (50), are gradually hydrolyzed during wintering and sprouting by increased levels of 7-glutamyl transpeptidase (75, 52, 53) and then oxidized to the cysteine sulfoxides [in onions, oxidation occurs first, resulting in accumulation of 7glutamyl-S-mwj-l-propenylcysteine sulfoxide, followed by transpeptidase hydrolysis to isoalliin (54)]. The same process occurs when garlic bulbs are stored at room temperature and is faster when stored cool (42, 48). The result is that store-purchased garlic cloves contain less 7-glutamylcysteines and more cysteine sulfoxides than freshpicked garlic (42, 48). The total sulfur content of garlic is about 1.0% of its dry weight or 0.35% of its fresh weight (55, 56). The cysteine sulfoxides (8-18 mg/g fresh wt.) and 7 glutamylcysteines (5-15 mg/g) account for about 82% of the total sulfur, with most of the remainder being present in soluble protein (3%), sulfate (5%), and insoluble compounds (6%) (Lawson, L . D . ; unpublished data). Small amounts of 5-2carboxypropylglutathione (0.09 mg/g) (57, 58), 7-glutamyl-5-allylmercaptocysteine (0.01 mg/g) (59), 7-glutamylmethionine (50), methionine (0.023 mg/g) (Lawson, L.D.; unpublished data), and scordinins (0.03 mg/g) (60) are also found. Undetected (
