![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Pathology and Microbiology, University of South Carolina School of Medicine and South Carolina Cancer Center, Columbia, SC
4 To whom correspondence should be addressed. E-mail: michael.wargovich{at}palmettohealth.org.
 |
ABSTRACT |
|---|
 TOP ABSTRACT DISCUSSIONLITERATURE CITED |
|---|
KEY WORDS: • garlic • colon cancer • CYP2E12e1 • carcinogenesis • chemoprevention
It has long been known that populations that have relied more on plants in their diets have lower risks for common cancers, such as those of the breast, colon, lung, and prostate (1). On the basis of these observations and a wealth of experimental evidence, national health agencies have taken a strong position on the benefits of adding fruits and vegetables to the diet in the hope of preventing chronic diseases (2). Although official dietary advice has not extended to particular herbs and spices, there has, again, been a wealth of studies indicating that these minor dietary components may harbor phytochemicals with significant biologic activity that can prevent cancer (3–5).
The aroma and taste of herbs and spices have always suggested health-promoting properties. Notable among the culinary herbs are members of the family Alliaceae, and probably the most popular of the edible alliums is garlic (Allium sativum). The characteristic odor and taste of garlic have fascinated chemists for years (6,7). As with any natural product, the responsible phytochemicals fall into water-soluble and lipid-soluble classes. Garlic derives its taste and smell through the generation of organosulfur compounds when cell walls of the bulb are breached (8). An enzyme, allinase, acts on a precursor molecule called alliin, forming allicin. Allicin is an unstable compound that breaks down under a variety of conditions, especially heat, to generate the myriad organosulfur compounds responsible for garlic's culinary and medicinal properties (9–11). Through the work of food chemists seeking flavorings for processed foods, many organosulfur compounds have made been available for research purposes. However, it must be remembered that the garlic bulb generates these molecules when the cell wall is compromised to elicit a response to injury. Garlic and its constituents have antibacterial, antifungal, and antiviral properties (12). Some of these compounds that enhance the survival of the plant may help to prevent cancer in humans. Animal models for cancer have been widely used as an intermediate step toward an understanding of how phytochemicals might have preventive effects in humans.
Garlic constituents: effects in animal cancer models. Because of the general availability of purified organosulfur compounds from garlic, many of them have been tested in animal models for cancer (13–18). A partial list of the garlic constituents that have been investigated in animal models is shown in Table 1. As stated above, garlic phytochemicals have been classified into water-soluble and lipid-soluble compounds, with the preponderance of research involving the lipid-soluble compounds. Not all studies have used separated components; some have used dried garlic or garlic powder. Some of the model systems in which these agents have been tested are shown in Table 2. Whereas many garlic constituents have been investigated in animal cancer models, the studies involving diallylsulfide listed in Table 2 are chosen to illustrate one probable mechanism of action that accounts for the widespread chemopreventive activity that has been observed in these systems, although other mechanisms certainly are involved.
|
|
Studies of structure-activity relations have indicated that dimethylhydrazine or azoxymethane induces colonic tumors through a process involving many steps, one of which involves aberrant crypt foci. In extending studies from nucleotoxicity to more bona-fide lesions, the same relation holds up: tests on diallylsulfide, allylmethyl, allylpropyl, and dipropylsulfide indicate that a single allyl side chain linked to a sulfur atom appears to inhibit carcinogenesis dramatically. An examination of a variety of naturally occurring water-soluble compounds and synthesized analogs of garlic compounds suggests that the allyl group is a critical determinant for the suppression of premalignant lesions induced by azoxymethane. Our findings suggest that CYP2E1 is inhibited by this particular carcinogen, and this effect serves as a model for several nitrosamines, including dimethylnitrosamine, diethylnitrosamine, liver carcinogens, colon carcinogens, and small-bowel carcinogens.
F344 rats have been used for the majority of studies on the chemopreventive effects of garlic. In these experiments; these animals are administered clearly defined semipurified diets, with the only variable being an oral dose of diallylsulfide or other garlic compounds. We have found that oral doses in excess of 50 mg/kg effectively shut down the CYP2E1 protein, indicating that 50 mg/kg is the inflection point in animal studies in which this CYP can be suppressed. Suppression of CYP2E1 in our studies effectively occurs by 
24 h after administration, which may possibly reflect what would happen if garlic were consumed on a daily basis.
Diallylsulfide is one of the more effective garlic compounds in terms of shutting down the CYP2E1 protein, as is diallyldisulfide. The propyl allyl compounds, however, are not effective as inhibitors for CYP2E1. With regard to transcription and posttranscriptional activity, the lipophilic garlic compounds do not appear to have any effect on mRNA levels; however, there is an effect on synthesis of proteins, suggestive of a possible mechanism.
In terms of the water-soluble garlic compounds, studies of structure-activity relations indicate that, again, an allyl compound attached to sulfur with a methyl group is one of the strongest inhibitors of the CYP2E1 protein. Interestingly, s-allylcysteine is not a very good inhibitor of CYP2E1. In a comparison of the water-soluble compounds with the lipophilic compounds with regard to potency, the lipophilic compounds have been found to be much more potent. As is the case with the lipophilic compounds, the water-soluble compounds of garlic do not appear to have an effect on CYP2E1 mRNA.
Our research has also addressed the effects of sustained exposure to oil-soluble garlic compounds. Short-term exposure to diallylsulfide results in a rapid functional loss of CYP2E1, and we have used F344 rats as a proxy to mimic human chronic exposure to these compounds over an extended period. A strong suppression of CYP2E1 protein is observed after 4 wk of animal exposure by oral intubation, and by 8 wk of sustained suppression, the influence of CYP2E1 is eliminated. This raises questions regarding potential interactions with drugs or low-molecular-weight compounds that are metabolized through CYP2E1 and regarding the effects of garlic in a long-term situation in which CYP2E1 is not present. Longer-term studies have suggested that liver damage could ensue under these conditions. A comparison of allylmethylsulfide and diallylsulfide indicates that over time, diallylsulfide increases liver weight. Histologic studies indicate that some cholangitis is evident in diallylsulfide-treated animals in their livers after at least 8 wk. This is unlikely to be of concern in humans, because the doses of sulfur compounds used in these trials are much higher than those in typical exposure to humans, as are the doses of carcinogen. Additional research has shown that diallylsulfide is a very effective substrate for CYP2E1 and goes through several passes in the liver, producing diallylsulfoxide and diallylsulfone, which are eventually ubiquitinated and destined for proteosomal degradation (23).
|
DISCUSSION |
|---|
|
TOPABSTRACTDISCUSSIONLITERATURE CITED |
|---|
This observation also explains the results in many classic animal models. Induction of glutathione-s-transferases and other detoxification enzymes may not be specific to garlic and its constituents but is generally related to xenobiotics in plants. However, sulfur chemistry appears to dictate induction of this class of enzymes. Inhibition of CYP2E1 may not be relevant in human cancers, except where exposure to low-molecular-weight aliphatic carcinogens is known or suspected. There is some concern about side effects (e.g., acetaminophen metabolism). The future development of genetic models of cancer may reveal more about garlic's true chemopreventive potential.
|
FOOTNOTES |
|---|
2 Author disclosure: No relationships to disclose.
3 Studies were supported by grants from the American Institute for Cancer Research.
5 Abbreviation used: CYP2E1, cytochrome p4502E1.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTDISCUSSIONLITERATURE CITED |
|---|
1. American Institute for Cancer Research. Food, Nutrition, and the Prevention of Cancer: a global perspective. Washington (DC): American Institute for Cancer Research; 1997.
2. Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA, Travis RC. Diet, nutrition and the prevention of cancer. Public Health Nutr. 2004;7:187–200.[Medline]
3. Adlercreutz H. Phyto-estrogens and cancer. Lancet Oncol. 2002;3:364–73.[Medline]
4. Lamartiniere CA, Cotroneo MS, Fritz WA, Wang J, Mentor-Marcel R, Elgavish A. Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate. J Nutr. 2002;132:552S–8S.
5. Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr. 2002;22:19–34.[Medline]
6. Lawson LD. The composition and chemistry of garlic cloves and processed garlic. In: Koch HP, et al., editors. Garlic: the science and therapeutic application of Allium sativum L. and related species. Baltimore: Williams & Wilkins; 1996. p. 37–108.
7. Pentz R, Siegers CP. Garlic preparations: methods for qualitative and quantitative assessment of their ingredients. In: Koch HP, et al., editors. Garlic: the science and therapeutic application of Allium sativum L. and related species. Baltimore: Williams & Wilkins; 1996. p. 109–34.
8. Milner JA. A historical perspective on garlic and cancer. J Nutr. 2001;131:1027S–31S.
9. Wargovich MJ. Colon cancer chemoprevention with ginseng and other botanicals. J Korean Med Sci. 2001;16: Suppl:S81–6.
10. Dorant E, van den Brandt PA, Goldbohm RA, Hermus RJ, Sturmans F. Garlic and its significance for the prevention of cancer in humans: a critical view. Br J Cancer. 1993;67:424–9.[Medline]
11. Lawson LD, Wang ZJ, Hughes BG. Identification and HPLC quantitation of the sulfides and dialk(en)yl thiosulfinates in commercial garlic products. Planta Med. 1991;57:363–70.[Medline]
12. Harris JC, Cottrell SL, Plummer S, Lloyd D. Antimicrobial properties of Allium sativum (garlic). Appl Microbiol Biotechnol. 2001;57:282–6.[Medline]
13. Wargovich MJ, Chang P, Velasco M, Sinicrope F, Eisenbrodt E, Sellin J. Expression of cellular adhesion proteins and abnormal glycoproteins in human aberrant crypt foci. Appl Immunohistochem Mol Morphol. 2004;12:350–5.[Medline]
14. Sumiyoshi H, Wargovich MJ. Chemoprevention of 1,2-dimethylhydrazine-induced colon cancer in mice by naturally occurring organosulfur compounds. Cancer Res. 1990;50:5084–7.
15. Wargovich MJ. Diallyl sulfide, a flavor component of garlic (Allium sativum), inhibits dimethylhydrazine-induced colon cancer. Carcinogenesis. 1987;8:487–9.
16. Wargovich MJ, Imada O, Stephens LC. Initiation and postinitiation chemopreventive effects of diallyl sulfide in esophageal carcinogenesis. Cancer Lett. 1992;64:39–42.[Medline]
17. Perchellet JP, Perchellet EM, Belman S. Inhibition of DMBA-induced mouse skin tumorigenesis by garlic oil and inhibition of two tumor-promotion stages by garlic and onion oils. Nutr Cancer. 1990;14:183–93.[Medline]
18. Sparnins VL, Barany G, Wattenberg LW. Effects of organosulfur compounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione S-transferase activity in the mouse. Carcinogenesis. 1988;9:131–4.
19. Xu C, Li CY, Kong AN. Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res. 2005;28:249–68.[Medline]
20. Gonzalez FJ. Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1. Mutat Res. 2005;569:101–10.[Medline]
21. Sohn OS, Ishizaki H, Yang CS, Fiala ES. Metabolism of azoxymethane, methylazoxymethanol and N-nitrosodimethylamine by cytochrome P450IIE1. Carcinogenesis. 1991;12:127–31.
22. Morimoto M, Hagbjork AL, Nanji AA, Ingelman-Sundberg M, Lindros KO, Fu PC, Albano E, French SW. Role of cytochrome P4502E1 in alcoholic liver disease pathogenesis. Alcohol. 1993;10:459–64.[Medline]
23. Brady JF, Ishizaki H, Fukuto JM, Lin MC, Fadel A, Gapac JM, Yang CS. Inhibition of cytochrome P-450 2E1 by diallyl sulfide and its metabolites. Chem Res Toxicol. 1991;4:642–7.[Medline]
24. Wargovich MJ. Inhibition of gastrointestinal cancer by organo-sulfur compounds in garlic. In: Wattenberg LW, et al., editors. Cancer chemoprevention. Boca Raton (FL): CRC Press; 1992. p.195–203.
25. Wattenberg LW, Sparnins VL, Barany G. Inhibition of N-nitrosodiethylamine carcinogenesis in mice by naturally occurring organosulfur compounds and monoterpenes. Cancer Res. 1989;49:2689–92.
26. Sparnins VL, Barany GL, Wattenberg LW. Effects of organosulfur compounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione S-transferase activity in the mouse. Carcinogenesis. 1988:131–4.
27. Hong JY, Wang ZY, Smith TJ, Zhou S, Shi S, Pan J, Yang CS. Inhibitory effects of diallyl sulfide on the metabolism and tumorigenicity of the tobacco-specific carcinogen 4- (methylnitosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mouse lung. Carcinogenesis. 1992;13:901–4.
28. Haber D, Siess MH, Canivenc-Lavier MC, Le Bon AM, Suschetet M. Differential effects of dietary diallyl sulfide and diallyl disulfide on rat intestinal and hepatic drug-metabolizing enzymes. J Toxicol Environ Health. 1995;44:423–34.[Medline]
29. Wargovich MJ, Woods C, Eng VW, Stephens LC, Gray K. Chemoprevention of N-nitrosomethylbenzylamine-induced esophageal cancer in rats by the naturally occurring thioether, diallyl sulfide. Cancer Res. 1988;48:6872–5.
30. Sengupta A, Ghosh S, Das S. Tomato and garlic can modulate azoxymethane-induced colon carcinogenesis in rats. Eur J Cancer Prev. 2003;12:195–200.[Medline]
31. Amagase H, Schaffer EM, Milner JA. Dietary components modify the ability of garlic to suppress 7,12-dimethylbenz(a)anthracene-induced mammary DNA adducts. J Nutr. 1996;126:817–24.
32. Schaffer EM, Liu JZ, Green J, Dangler CA, Milner JA. Garlic and associated allyl sulfur components inhibit N-methyl-N-nitrosourea induced rat mammary carcinogenesis. Cancer Lett. 1996;102:199–204.[Medline]
33. Singh A, Shukla Y. Antitumour activity of diallyl sulfide on polycyclic aromatic hydrocarbon-induced mouse skin carcinogenesis. Cancer Lett. 1998;131:209–14.[Medline]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
