Organosulfur Compounds From Garlic

S-(+)-Alkyl-L-cysteine sulfoxides from Garlic

y-L-Glutamyl-S-alkyl-L-cysteines from Garlic

The Cysteine sulfoxides and the y-Glutamylcysteines are the major organosulfur compounds in whole, unbruised Garlic. They are present in roughly equal amounts by weight. Together, they contain some 95% of the total sulfur in Garlic and add up to an average of 20 mg/g of fresh Garlic or about 40 to 80 mg per clove.

Within the Garlic bulb, during storage and sprouting, a portion of the y-Glutamylcysteines are converted into the cysteine sulfoxides. Alliin is by far the most abundant of the cysteine sulfoxides (5-14 mg/g), followed by methiin at 0.5-2.0 mg/g, isoalliin at 0.2-1.2 mg/g, and cycloalliin at 0.5-1.5 mg/g.

Of the y-Glutamylcysteines, y-Glutamyl-S-trans-1-propenylcysteine is usually the most abundant (3-9 mg/g), followed by y-Glutamyl-S-allylcysteine (2-6 mg/g) and y-Glutamyl-S-methylcysteine (sometimes present, at 0.1-0.4 mg/g) (fresh weight values). In Garlic powders, y-Glutamyl-S-allylmercaptocysteine is also found. An average of ~12 mg/g total y-Glutamylcysteines was found in a study of commercial Garlic powder tablets¹. The other known bioactive sulfur compounds in Garlic are derived from the cysteine sulfoxides and the y-Glutamylcysteines.

Alliin, Isoalliin, and Methiin are Precursors of the Thiosulfinates

The enzyme alliinase (alliin lyase; EC 4.4.1.4) acts upon the cysteine sulfoxides alliin (S-2-propenylcysteine sulfoxide), isoalliin (S-trans-1-propenylcysteine), and methiin (S-methylcysteine sulfoxide) to form sulfenic acid intermediates.   The intermediates rapidly self-condense, resulting in the eight known dialkyl thiosulfinates in crushed Garlic. A typical measurement of the relative abundance of each thiosulfinate (by weight) is²:

Allicin, 70%
Allyl methane THS, 12%
trans-1-Propenyl 2-propene THS, 6%
Methyl 2-propene THS, 6%
Allyl trans-1-Propene THS, 2%
Methyl methane THS, 2%
trans-1-Propenyl methane THS, 1.5%
Methyl trans-1-Propene THS, 0.5%

Cycloalliin is unavailable to the enzyme alliinase, and so is not transformed into thiosulfinates.

The five chemical names for allicin are:
1. Allicin
2. Diallyl thiosulfinate
3. Allyl 2-propenethiosulfinate
4. 2-propenyl 2-propenethiosulfinate
5. 2-propene1-1sulfinothioic acid S-2-propenyl ester

Depending on their chemical environment, the thiosulfinates are transformed into sulfides, vinyldithiins, or ajoene.

Major Transformation Products of the Cysteine sulfoxides and y-Glutamylcysteines from Garlic

Cycloalliin

From Alliin, Methiin, and Isoalliin via Thiosulfinates

From y-Glutamylcysteines

Not transformed
during processing

Steam distilled Garlic oil [also occur in Garlic + water]

Oil macerate (i.e., Garlic minced in Olive oil)

Aged ethanol extract

Diallyl trisulfide

Ajoene

S-Allylcysteine

Diallyl disulfide

1,3-Vinyldithiin

S-1-Propenylcysteine

Allyl methyl trisulfide

1,2-Vinyldithiin

S-Allylmercaptocysteine

Allyl methyl disulfide

Transformation Products of Thiosulfinates in Water

In crushed Garlic, the thiosulfinates spontaneously transform into sulfides. The major sulfides formed are diallyl trisulfide, diallyl disulfide and allyl methyl trisulfide.

In steam-distilled Garlic oil, about twenty variations on the sulfides have been identified. The most abundant in commercial brands are diallyl disulfide (~ 26%)*, diallyl trisulfide (~18%), allyl methyl trisulfide (~15%), allyl methyl disulfide (~12%), diallyl tetrasulfide (~8%), allyl methyl tetrasulfide (~6%). The other compounds which are present at concentrations less than 5% are diallyl mono-, penta-, and hexasulfides; allyl methyl mono-, penta- and hexasulfides; dimethyl di-, tri-, tetra-, penta-, and hexasulfides and allyl 1-propenyl di- and trisulfides.³ 

These compounds have very low water solubility. They are considerably more stable than their parent compounds; the sulfide composition of steam-distilled Garlic oil capsules changes very little over a number of years.

The Garlic sulfides have exhibited antibiotic, anticancer, anti-inflammatory, antioxidant, antiparasitic, and antithrombotic effects,⁴ and modulatory effects on hepatic detoxification enzymes.^5,6,7 A PubMed search on "garlic sulfide" reveals 287 studies as of 11/2003.



* Weight % of total sulfur compounds in steam-distilled Garlic oil.

Transformation Products of Thiosulfinates in Oils
and Alcohol

In oil macerates, the thiosulfinates form dithiins, ajoene, and sulfides. The major products are 1,3-vinyldithiin (2-vinyl-4H-1,3-dithiin); 1,2-vinyldithiin (3-vinyl-4H-1,2-dithiin); allyl sulfides; and ajoene (E,Z-4,5,9-trithiadodeca-1,6,11-triene 9-oxide). 1,3-vinyldithiin is the most abundant compound (~ 50%), with roughly equal amounts of the others present.

In a study of typical European commercial oil-macerate capsules, 1,2-vinyldithiin was especially stable, showing little change over five years, and 1,3-vinyldithiin decreased by an average of 24% over the same time period. Ajoene was far less stable, decreasing by a rate of 1.5% per month and being completely transformed by five years.⁸

In ethanol extraction of crushed Garlic, allicin yields diallyl trisulfide (73%), diallyl disulfide (8%), and ajoene (8%)*. The proportions of these and other compounds vary with concentration of alcohol and aging of the extract⁹.

Ajoene has demonstrated anticancer,^10,30 antibiotic, antioxidant, antithrombotic, and hypotensive effects.¹¹ The vinyldithiins have demonstrated antibiotic,¹² anti-aggregatory,¹³ anticancer,¹⁴ and anticholesterolemic¹⁵ effects. Ninety-nine studies indexed on PubMed address the dithiins and ajoene.
 

* Percentages of total compounds formed from allicin transformation.

Transformation Products of the y-Glutamylcysteines

The y-Glutamylcysteines found in whole Garlic are not affected when the cloves are crushed. In cloves dried for powdering, S-allylcysteine and S-trans-1-propenylcysteine are found at a concentration of ~2.7-5 mg/g collectively. Neither y-Glutamylcysteines nor their transformation products are found in steam-distilled Garlic oils or oil-macerates.

In  a 20% ethanol extract aged in the laboratory for 12 months, the following water-soluble transformation products were found: S-allylcysteine at ~7 mg/g; S-trans-1-propenylcysteine at ~ 6.5 mg/g; and S-allylmercaptocysteine at ~ 2 mg/g (dry weight).¹⁶ These values represent a large increase over the levels of these compounds present when the extract was first made. A study by Lawson and Wang indicated that the S-allylcysteine in the ethanol extracts remained stable for 2 years, while the levels of S-trans-1-propenylcysteine declined by ~45% in that time.¹⁷

S-allylcysteine has been studied extensively. Researchers have found antioxidant, anticancer, and antihepatotoxic effects.¹⁸ A PubMed search on <S-allylcysteine> finds 62 papers as of 11/2003. Searching on <S-allylmercaptocysteine> locates 18 studies, which have discovered antioxidant,^19,20 anticancer,^21,22 and antihepatotoxic^23,24 effects for this compound as well. Update: New research on S-allylmercaptocysteine examines its ability to induce apoptosis in colon cancer cells: Induction of Apoptosis by the Garlic-Derived Compound S-Allylmercaptocysteine (SAMC) Is Associated with Microtubule Depolymerization and c-Jun NH2-Terminal Kinase 1 Activation (Cancer Research).

Pharmacokinetics of Organosulfur Compounds in Garlic

 Once absorbed, allicin and its transformation products are rapidly metabolized. Allicin, diallyl trisulfide, diallyl disulfide, S-allylmercaptocysteine, and ajoene have all been demonstrated to form allyl mercaptan when exposed to human blood, in vitro²⁵ and presumably in vivo as well. It appears that some allyl mercaptan is further metabolized to allyl methyl sulfide²⁶ (and minor amounts of dimethyl disulfide), which are excreted from the lungs. Allyl mercaptan and methyl mercaptan have also been found in the breath.²⁷ Diallyl disulfide, diallyl sulfide, and dimethyl disulfide have been found in urine after Garlic oil ingestion.²⁸ One recent in vitro study indicates that diallyl disulfide can be metabolized to allicin in human liver cells.²⁹

The y-Glutamylcysteines are thought to be metabolized in the kidney to S-allylcysteine and S-1-propenylcysteine. Metabolites of these have been detected in the urine. There is a great deal that yet remains to be discovered concerning the metabolites of the various Garlic compounds.

References

1. Lawson, L. D. In: Garlic: the Science and Therapeutic Application of Allium sativum L. and Related Species; Koch, H. P.; Lawson, L. D. Eds. Williams & Wilkins: Baltimore, 1996; pp 37-107.
2. Ibid, p. 43.
3. Lawson, L. D.; Wang Z. J.; Hughes B. G. Planta Medica 1991 57: 363-370.
4. Reuter, H. D.; Koch, H. P.; Lawson, L. D. In: Garlic: the Science and Therapeutic Application of Allium sativum L. and Related Species; Koch, H. P.; Lawson, L. D. Eds. Williams & Wilkins: Baltimore, 1996; pp 135-212.
5. Wu, C. C. et al. J Agric Food Chem 2002 50: 378-83.
6. Loizou, G. D.; Cocker, J. Human and Experimental Toxicology 2001 7: 321-7.
7. Guyonnet, D. et al. Mutation Research 2001 495: 135-45.
8. Lawson, 1996.
9. Lawson, 1996..
10. Ahmed, N. et al. 2001 Anticancer Research 5: 3519-23.
11. Reuter, 1996
12. Ibid, p. 163.
13. Nishimura, H. et al. Biofactors 2000 13: 257-63.
14. Lee, K. T. et al. Archives of Pharmacal Research 2001 24: 44-50.
15. Sendl, A. et al. Planta Medica 1992 58: 8-13.
16. Lawson, 1996.
17. Lawson, L. D.; Wang, Z. J. Journal of Toxicology 1995 14:214.
18. Reuter, 1996.
19. Imai, J. et al. Planta Medica 1994 60: 417-20.
20. Borek, C. Journal of Nutrition 2001 131: 1010S-5S.
21. Shirin, H. et al. Cancer Research 2001 61: 725-31.
22. Pinto, J. T. et al. The Prostate 2000 45: 304-14.
23. Sumioka et al. European Journal of Pharmacology 2001 433: 177-85.
24. Sumioka et al. Japanese Journal of Pharmacology 1998 78: 199-207.
25. Koch, H. P. In: Garlic: the Science and Therapeutic Application of Allium sativum L. and Related Species; Koch, H. P.; Lawson, L. D. Eds. Williams & Wilkins: Baltimore, 1996; pp. 213-220.
26. Rosen, R. T. et al. Biofactors 2000 13: 241-9.
27. Tamaki, T.; Sonoki, S. Journal of Nutritional Science and Vitaminology 1999 45: 213-22.
28. Koch, 1996.
29. Teyssier, C. et al. Drug Metabolism and Disposition 1999 27: 835-41.
30. Tilli, C. M. et al. The garlic-derived organosulfur component ajoene decreases basal cell carcinoma tumor size by inducing apoptosis. Arch Dermatol Res 2003 May 20 E pub: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12756587&dopt=Abstract

References to new studies on Garlic constituents

Chung JG, Lu HF, Yeh CC, Cheng KC, Lin SS, Lee JH. Inhibition of N-acetyltransferase activity and gene expression in human colon cancer cell lines by diallyl sulfide. Food Chem Toxicol. 2004 42: 201-8. PMID: 14667466

Liu ZF, Fang F, Dong YS, Li G, Zhen H. Experimental study on the prevention and treatment of murine cytomegalovirus hepatitis by using allitridin. Antiviral Res. 2004 61: 125-8. PMID: 14670586

Velmurugan B, Bhuvaneswari V, Nagini S. Effect of S-allylcysteine on oxidant-antioxidant status during N-methyl-N'-nitro-N-nitrosoguanidine and saturated sodium chloride-induced gastric carcinogenesis in Wistar rats. Asia Pac J Clin Nutr. 2003 12: 488-94. PMID: 14672876

2006 A novel anticancer effect of garlic derivatives: inhibition of cancer cell invasion through restoration of E-cadherin expression.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16675472&query_hl=11&itool=pubmed_Summary

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