Documente Academic
Documente Profesional
Documente Cultură
ABSTRACT Eight water-soluble components of aged garlic extract were evaluated to assess their potential to in-
hibit the activity of human cytochrome-P450 (CYP) enzymes. The in vitro model consisted of human liver microsomes
with index reactions chosen to profile the activity of the following six CYP isoforms: CYP1A2, 2B6, 2C9, 2C19, 2D6,
and 3A. With only 2 exceptions, none of the 8 garlic components produced .50% inhibition even at high concentrations
(100 mmol/L). S-methyl-L-cysteine and S-allyl-L-cysteine at 100 mmol/L produced modest inhibition of CYP3A, reduc-
ing activity to 20–40% of control. However available clinical evidence does not indicate CYP3A inhibition in vivo.
KEY WORDS: aged garlic extract Cytochromes P450 in vitro metabolism drug interaction
The increasingly extensive utilization of complementary or and adverse effects of these agents such that consumers and
alternative medical therapies over the last decade is now well health care providers will have the information available to
documented (1–7). This incorporates the use of botanical maximize therapeutic benefits of botanicals while minimizing the
medicines either alone or in combination with prescription likelihood of unwanted effects.
medications. With the increased prevalence of botanical use Commercial promotion of botanicals usually emphasizes that
comes the need for clinical and scientific data on the phar- they are ‘‘safe,’’ ‘‘natural,’’ and contain ‘‘no chemicals.’’ In fact,
macologic properties, mechanisms of action, drug interactions, plant systems have their own metabolic processes, and human
evolution has created processes to biotransform and eliminate
ingested plants. As such, plants can induce, inhibit, or be toxic
1
Published in a supplement to The Journal of Nutrition. Presented at the to human metabolic systems, and seemingly safe and natural
symposium ‘‘Significance of Garlic and Its Constituents in Cancer and Cardiovas- plant products may have predictable influences on human drug
cular Disease’’ held April 9–11, 2005 at Georgetown University, Washington, DC.
The symposium was sponsored by Strang Cancer Prevention Center, affiliated metabolism. Of particular concern are the increasing numbers
with Weill Medical College of Cornell University, and Harbor-UCLA Medical Center, of clinical and scientific reports of drug interactions involving
and co-sponsored by American Botanical Council, American Institute for Cancer botanical products (8–19). Some of these interactions, for
Research, American Society for Nutrition, Life Extension Foundation, General
Nutrition Centers, National Nutritional Foods Association, Society of Atheroscle- example, those involving St. John’s wort, are of major clinical
rosis Imaging, Susan Samueli Center for Integrative Medicine at the University of importance. Mechanisms investigated to date include the
California, Irvine. The symposium was supported by Alan James Group, LLC, possibility that botanical medicines may induce or inhibit the
Agencias Motta, S.A., Antistress AG, Armal, Birger Ledin AB, Ecolandia Inter-
nacional, Essential Sterolin Products (PTY) Ltd., Grand Quality LLC, IC Vietnam, activity of human Cytochrome P450 enzymes or the activity of
Intervec Ltd., Jenn Health, Kernpharm BV, Laboratori Mizar SAS, Magna Trade, transport proteins such as P-glycoprotein (20). Because the
Manavita B.V.B.A., MaxiPharm A/S, Nature’s Farm, Naturkost S. Rui a.s., Nichea number of botanical medicines in clinical use is very large, it is
Company Limited, Nutra-Life Health & Fitness Ltd., Oy Valioravinto Ab, Panax, PT.
Nutriprima Jayasakti, Purity Life Health Products Limited, Quest Vitamins, Ltd.,
simply not feasible to conduct clinical studies for all possible
Sabinco S.A., The AIM Companies, Valosun Ltd., Wakunaga of America Co. Ltd., drug interactions that need to be studied and understood.
and Wakunaga Pharmaceutical Co., Ltd. Guest editors for the supplement Accordingly, there are now large gaps in knowledge, and rec-
publication were Richard Rivlin, Matthew Budoff, and Harunobu Amagase. Guest
Editor Disclosure: R. Rivlin has been awarded research grants from Wakunaga
ommendations regarding which drug combinations with bo-
of America, Ltd. and received an honorarium for serving as co-chair of the tanicals are safe or unsafe are often based on incomplete data.
conference; M. Budoff has been awarded research grants from Wakunaga of An extensive literature supports the existence of the ther-
America, Ltd. and received an honorarium for serving as co-chair of the apeutically beneficial effects of garlic preparations in the preven-
conference; and Harunobu Amagase is employed by Wakunaga of America, Ltd.
2
Author disclosure: No relationships to disclose. tion of atherogenesis and neoplastic disease (21–31). A number
3
This work was supported in part by grants AT-01381, AI-55412, MH-58435, of components in garlic are postulated to act synergistically to
DA-13209, DK/AI-58496, DA-13834, AG-17880, AI-58784, and RR-00054 from the provide these health benefits (32–39). Due to the complex
U.S. Department of Health and Human Services.
4
To whom correspondence should be addressed: E-mail: dj.greenblatt@ chemistry of garlic, variations in processing yield quite different
tufts.edu. preparations. Highly unstable thiosulfinates, such as allicin,
806S
WATER-SOLUBLE GARLIC AND HUMAN CYTOCHROMES P450 807S
TABLE 1
Experimental conditions for inhibition studies
disappear during processing and are quickly and extensively The present study utilized the in vitro model to screen for
transformed (34). Efficacy and safety are also contingent upon potential inhibitory metabolic effects of a number of compo-
processing methods. The process of extraction has been assumed nents of aged garlic extract.
to increase the potency and bioavailability of various crude herbs
and eliminate their harsh and toxic characteristics. The
irritating, acidic, and oxidizing compounds in raw garlic can be METHODS
eliminated and modified through the extraction process. In fact,
Liver samples from individual human donors with no known
TABLE 2
Effect of aged garlic extract components on activity of human
Cytochrome P450 isoforms in vitro
Alliin — — — — — —
Cycloalliin — — — — — —
Methylin — — — — — —
S-Methyl-L-cysteine 1 — — — — —
SAC 1 — — — — —
N-Acetyl-SAC — — — — — —
S-Allomercapto-L-cysteine — — — — — —
Gamma-glutamyl-SAC — — — — — —
11. Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment 44. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the
of report reliability. Br J Clin Pharmacol. 2001;52:587–95. likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet. 1997;32:
12. Scott GN, Elmer GW. Update on natural product–drug interactions. Am J 210–58.
Health Syst Pharm. 2002;59:339–47. 45. von Moltke LL, Greenblatt DJ, Schmider J, Wright CE, Harmatz JS,
13. Valli G, Giardina EG. Benefits, adverse effects and drug interactions of Shader RI. In vitro approaches to predicting drug interactions in vivo. Biochem
herbal therapies with cardiovascular effects. J Am Coll Cardiol. 2002;39:1083–95. Pharmacol. 1998;55:113–22.
14. Ernst E. The risk-benefit profile of commonly used herbal therapies: 46. Venkatakrishnan K, von Moltke LL, Obach RS, Greenblatt DJ. Drug
Ginkgo, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto, and Kava. Ann Intern metabolism and drug interactions: application and clinical value of in vitro models.
Med. 2002;136:42–53. Curr Drug Metab. 2003;4:423–59.
15. Ioannides C. Pharmacokinetic interactions between herbal remedies and 47. Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J,
medicinal drugs. Xenobiotica. 2002;32:451–78. King SP, Miwa G, et al. The conduct of in vitro and in vivo drug-drug interaction
16. De Smet PA. Health risks of herbal remedies: an update. Clin Pharmacol studies: a PhRMA perspective. J Clin Pharmacol. 2003;43:443–69.
Ther. 2004;76:1–17. 48. von Moltke LL, Greenblatt DJ, Duan SX, Schmider J, Kudchadker L,
17. Sparreboom A, Cox MC, Acharya MR, Figg WD. Herbal remedies in the Fogelman SM, Harmatz JS, Shader RI. Phenacetin O-deethylation by human liver
United States: potential adverse interactions with anticancer agents. J Clin Oncol. microsomes in vitro: inhibition by chemical probes, SSRI antidepressants,
2004;22:2489–503. nefazodone, and venlafaxine. Psychopharmacology (Berl). 1996;128:398–407.
18. Coxeter PD, McLachlan AJ, Duke CC, Roufogalis BD. Herb-drug inter- 49. von Moltke LL, Greenblatt DJ, Harmatz JS, Duan SX, Harrel LM, Cotreau-
actions: an evidence based approach. Curr Med Chem. 2004;11:1513–25. Bibbo MM, Pritchard GA, Wright CE, Shader RI. Triazolam biotransformation by
19. Foster BC, Arnason JT, Briggs CJ. Natural health products and drug human liver microsomes in vitro: effects of metabolic inhibitors, and clinical
disposition. Annu Rev Pharmacol Toxicol. 2005;45:203–26. confirmation of a predicted interaction with ketoconazole. J Pharmacol Exp Ther.
20. Zhou S, Gao Y, Jiang W, Huang M, Xu A, Paxton JW. Interactions of 1996;276:370–9.
herbs with cytochrome P450. Drug Metab Rev. 2003;35:35–98. 50. von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS, Shader RI. Inhibition
21. Caron MF, White CM. Evaluation of the antihyperlipidemic properties of of triazolam hydroxylation by ketoconazole, itraconazole, hydroxyitraconazole and
dietary supplements. Pharmacotherapy. 2001;21:481–7. fluconazole in vitro. Pharm Pharmacol Commun. 1998;4:443–5.
22. Dorant E, van den Brandt PA, Goldbohm RA, Hermus RJ, Sturmans F. 51. Perloff MD, von Moltke LL, Court MH, Kotegawa T, Shader RI, Greenblatt
Garlic and its significance for the prevention of cancer in humans: a critical view. DJ. Midazolam and triazolam biotransformation in mouse and human liver
Br J Cancer. 1993;67:424–9. microsomes: relative contribution of CYP3A and CYP2C9 isoforms. J Pharmacol
23. Wang HX, Ng TB. Natural products with hypoglycemic, hypotensive, Exp Ther. 2000;292:618–28.
hypocholesterolemic, antiatherosclerotic and antithrombotic activities. Life Sci. 52. Giancarlo GM, Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt
1999;65:2663–77. DJ. Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: