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Plant Profiler

Chaparral (Larrea divaricata)


Chaparral (Larrea divaricata) Image
Synonyms / Common Names / Related Terms
1 aryl tetralin lignans, chaparral taxa, chaparral tea, chaparro, creosote, creosote bush, dwarf evergreen oak, el gobernadora, falsa alcaparra, flavonoids, furanoid lignans, geroop, gobernadora, greasewood, guaiaretic acid, guamis, gumis, hediondilla, hideonodo, hydrocarbons, jarillo, kovanau, kreosotstrauch, Larrea, Larrea divaricata, Larrea glutiosa, Larrea mexicana, Larrea mexicana Moric, lignans, maltose-M3N, M4N, NDGA, nordihydroguaiaretic acid, Nordy, palo ondo (Spanish), sapogenins, shoegoi, sonora covillea, sterols, tasago, triterpenes, volatile oils, wax esters, ya-temp, yah-temp, Zygophyllaceae (family).



Mechanism of Action

Pharmacology:

  • Constituents: The major components of the resinous coating of chaparral are lignans25,7,23, which can comprise up to 80% of some extracts of chaparral such as methanol extracts of green leaves or green stems26. Lignans are low molecular weight plant products made up of phenylpropanoid dimers or trimers. The major lignan in chaparral is nordihydroguaiaretic acid (NDGA).23,27 NDGA is a derivative of guaiaretic acid and is a catechol having two hydroxyl groups on each of the two phenol rings.
  • In addition to NDGA, chaparral contains guaiaretic acid and other substituted guaiaretic acid derivatives. Other lignans in chaparral are classified as furanoid lignans and 1aryl tetralin lignans. The latter are structurally related to podophyllotoxins. Chaparral contains flavonoids as non-water-soluble aglycones, as water-soluble glycosides, and as sulfated flavonoids.7 Chaparral also contains triterpenes, including sapogenins7, as well as volatile oils, wax esters, sterols, and other hydrocarbons7,28.
  • Many studies have shown that chaparral and NDGA possess antioxidant properties, exhibit cytotoxic properties in a variety of cell types, and inhibit enzymes important in cellular responses to hormones and other stimuli. NDGA has been shown to inhibit the induction of ornithine decarboxylase, a lipoxygenase inhibitor in mic29 and in vitro30.
  • Antimutagenic effects: In a study of norgestrel-induced genotoxic damage, NDGA reduced sister chromatid exchanges and chromosomal aberrations, and increased the mitotic and replication indices.15
  • Antineoplastic effects: NDGA has potential anti-tumor effects. Lignans isolated from the flowering tops of Larrea tridentata had IC50 values of 5-60mcM against human breast cancer, human colon cancer and human melanoma cell lines.16 In one study, stimulation of tumor growth was reported in a significant number of patients.11 However, NDGA caused cytotoxicity in human prostate cancer cells17 and reduced vascular endothelial growth factor expression18. Tetra-O-methyl nordihydroguaiaretic acid is a global transcription inhibitor20 that has been shown to suppress tumor growth in animal study31 and reverse the multidrug resistance of xenografted tumor cells21. A combination of nonsteroidal ant inflammatory drugs (NSAIDs), butyrate, indomethacin, and nordihydroguaiaretic acid (NDGA) was effective in inhibiting cell proliferation in the colon cancer cell line HT29.19 NDGA also inhibits the mitochondrial electron transport system; induces, enhances, or (in one case) inhibits apoptosis; alters certain cellular immune system responses; modifies biological responses to a variety of chemicals, including hormones; and has estrogenic activity.
  • Antioxidant effects: The chaparral constituent nordihydroguaiaretic acid (NDGA) has been theorized to block cellular respiration and exert antioxidant effects, although pharmacological studies are limited. Nordihydroguaiaretic acid has been used experimentally to induce cystic renal disease in rats. It may be extracted from the leaves of the creosote bush, which are consumed as chaparral tea in the southwestern United States.2 Lignans from the leaves of Larrea tridentata have been analyzed for antioxidant activities.23 Evidence suggests that the antioxidant properties of chaparral may involve a direct scavenging effect of the primary oxygen radical, O2*- in a dose-dependent manner.4 The lignan nordihydroguaiaretic acid frequently used as an antioxidant standard in experiments.24
  • Antiplatelet effects: NDGA diminishes platelet aggregation evoked by collagen or adenosinediphosphate and delays its onset.8
  • Antiviral effects: In a study of the replication of the influenza virus in infected human fetal membrane chorion cells, NDGA inhibited reactive oxygen species overproduction, apoptotic DNA fragmentation, and virus proliferation, with greater antiviral activity than pyrrolidine dithiocarbamate.5
  • Cytologic effects: Based on in vitro study, nordihydroguaiaretic acid (NDGA) seems to interrupt membrane traffic by affecting dynein-dyanactin function.32
  • Cytochrome P450 effects: Hydroxyl groups of NDGA may play a role in inhibiting cytochrome P450 monoxygenase activity.22 A plausible mechanism in both hepatotoxicity and nephrotoxicity is the cytochrome P450-dependent metabolism of NDGA to a toxic quinone with failure to remove this reactive metabolite by conjugation if glutathione is limiting. NDGA can be expected to be a substrate for cytochrome P450-dependent quinone formation based on its chemical structure, as well as evidence discussed by Obermeyer et al.6 These data are supported by the findings that NDGA inhibits prostaglandin synthesis, cyclooxygenase, and lipoxygenases.
  • Fatty acid synthase inhibition activity: NDGA has an IC50 for animal fatty acid synthase between five and 40mcM.33
  • Hepatic effects: Several case reports exist documenting hepatic effects of chaparral ingestion. Chaparral has been associated with acute nonviral toxic hepatitis and contains lignans that are structurally similar to known estrogenic compounds.6 In a case report, serum enzyme levels, including alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, and gamma-glutamyl transpeptidase, were markedly elevated after taking chaparral tablets.3 Permanent hepatic fibrosis was documented in a case report six months after liver function tests had normalized.10 Clinical presentation, characterized as jaundice with a marked increase in serum liver chemistry values, occurred 3-52 weeks after the ingestion of chaparral, and it resolved 1-17 weeks after most patients stopped their intake of chaparral.1 Five of 15 cases exhibited documented recovery after cessation of chaparral use and one case exhibited abnormal liver function upon re-challenge. In all the other cases, liver function tests became significantly abnormal with clinically evident jaundice that reversed upon discontinuation of chaparral use.
  • Hypoglycemic effects: In mouse models of type 2 diabetes, NDGA was shown to decrease plasma glucose concentrations, without any change in insulin concentration. NDGA improved glucose tolerance and ability of insulin to decrease glucose concentrations.9
  • Immune-stimulating effects: It has been suggested that chaparral contains immune-stimulating polysaccharides.

Pharmacodynamics/Kinetics:

  • Lignans isolated from the flowering tops of Larrea tridentata had IC50 values of 5-60mcM against human breast cancer, human colon cancer and human melanoma cell lines.16
  • Distribution: The kinetic parameters, IC50 and Vmax, for chaparral scavenging of O2*- were found to be 0.899mcg/mL and 8.4ng/mL/sec, respectively.4 The rate constant for chaparral scavenging O2*- was found to be 1.22 x 10(6) g(-1) s(-1).
  • Metabolism: In rats, the chaparral component nordihydroguaiaretic acid (NDGA) is metabolized to an o-quinone metabolite in the ileum, is absorbed in the bloodstream, filtered by the glomeruli, and retained by the proximal tubule where it accumulates.14,13,12 Free NDGA is not found in the rat kidney, but is found in the feces.12
  • Elimination: In female mice, NDGA was administered intravenously at 50mg/kg to yield a primary half-life (T1/2α) of 30 minutes and a secondary half-life (T1/2β) of 135 minutes with the peak plasma concentration (Cmax) being 15mcg/mL.34

References

  1. Sheikh, N. M., Philen, R. M., and Love, L. A. Chaparral-associated hepatotoxicity. Arch Intern Med 4-28-1997;157(8):913-919. 9129552
  2. Smith, A. Y., Feddersen, R. M., Gardner, K. D., Jr., and Davis, C. J., Jr. Cystic renal cell carcinoma and acquired renal cystic disease associated with consumption of chaparral tea: a case report. J Urol  1994;152(6 Pt 1):2089-2091. 7966683
  3. Alderman, S., Kailas, S., Goldfarb, S., Singaram, C., and Malone, D. G. Cholestatic hepatitis after ingestion of chaparral leaf: confirmation by endoscopic retrograde cholangiopancreatography and liver biopsy. J Clin Gastroenterol  1994;19(3):242-247. 7806838
  4. Zang, LY, Cosma, G, Gardner, H, Starks, K, Shi, X, and Vallyathan, V. Scavenging of superoxide anion radical by chaparral. Mol Cell Biochem 1999;196(1-2):157-161.
  5. Uchide, N., Ohyama, K., Bessho, T., and Toyoda, H. Inhibition of influenza-virus-induced apoptosis in chorion cells of human fetal membranes by nordihydroguaiaretic Acid. Intervirology 2005;48(5):336-340. 15956802
  6. Obermeyer, W. R., Musser, S. M., Betz, J. M., Casey, R. E., Pohland, A. E., and Page, S. W. Chemical studies of phytoestrogens and related compounds in dietary supplements: flax and chaparral. Proc Soc Exp Biol Med 1995;208(1):6-12. 7892296
  7. Mabry, TJ, Hunkiker, JH, and DiFeo, DR.Creosote Bush: Biology and Chemistry of Larrea in New World Deserts. Stroudsburg, PA: Dowden, Hutchinson & Ross;1977.
  8. Gimeno, M. F., Shattner, M. A., Borda, E., Gimeno, A. L., and Lazzari, M. A. Lipoxygenase inhibitors alter aggregation and adhesiveness of human blood platelets from aspirin-treated patients. Prostaglandins Leukot Med 1983;11(1):109-119. 6410411
  9. Luo, J., Chuang, T., Cheung, J., Quan, J., Tsai, J., Sullivan, C., Hector, R. F., Reed, M. J., Meszaros, K., King, S. R., Carlson, T. J., and Reaven, G. M. Masoprocol (nordihydroguaiaretic acid): a new antihyperglycemic agent isolated from the creosote bush (Larrea tridentata). Eur J Pharmacol 4-3-1998;346(1):77-79. 9617755
  10. Kauma, H., Koskela, R., Makisalo, H., Autio-Harmainen, H., Lehtola, J., and Hockerstedt, K. Toxic acute hepatitis and hepatic fibrosis after consumption of chaparral tablets. Scand J Gastroenterol  2004;39(11):1168-1171. 15545179
  11. Smart, C. R., Hogle, H. H., Vogel, H., Broom, A. D., and Bartholomew, D. Clinical experience with nordihydroguaiaretic acid--"chaparrel tea" in the treatment of cancer. Rocky Mt Med J 1970;67(11):39-43. 5480535
  12. Goodman, T., Grice, H. C., Becking, G. C., and Salem, F. A. A cystic nephropathy induced by nordihydroguaiaretic acid in the rat. Light and electron microscopic investigations. Lab Invest 1970;23(1):93-107. 5431225
  13. Grice, H. C., Becking, G., and Goodman, T. Toxic properties of nordihydroguaiaretic acid. Food Cosmet Toxicol  1968;6(2):155-161. 5671148
  14. De Smet, PAGM.In: De Smet, PAGM. Adverse Effects of Herbal Drugs. Berlin: Springer-Verlag;1993.
  15. Siddique, Y. H., Beg, T., and Afzal, M. Protective effect of nordihydroguaiaretic acid (NDGA) against norgestrel induced genotoxic damage. Toxicol In Vitro 2006;20(2):227-233. 16061348
  16. Lambert, J. D., Sang, S., Dougherty, A., Caldwell, C. G., Meyers, R. O., Dorr, R. T., and Timmermann, B. N. Cytotoxic lignans from Larrea tridentata. Phytochemistry 2005;66(7):811-815. 15797607
  17. Huang, J. K., Chen, W. C., Huang, C. J., Hsu, S. S., Chen, J. S., Cheng, H. H., Chang, H. T., Jiann, B. P., and Jan, C. R. Nordihydroguaiaretic acid-induced Ca2+ handling and cytotoxicity in human prostate cancer cells. Life Sci 9-24-2004;75(19):2341-2351. 15350831
  18. Nie, D., Krishnamoorthy, S., Jin, R., Tang, K., Chen, Y., Qiao, Y., Zacharek, A., Guo, Y., Milanini, J., Pages, G., and Honn, K. V. Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells. J Biol Chem 7-7-2006;281(27):18601-18609. 16638750
  19. Galfi, P., Neogrady, Z., Amberger, A., Margreiter, R., and Csordas, A. Sensitization of colon cancer cell lines to butyrate-mediated proliferation inhibition by combined application of indomethacin and nordihydroguaiaretic acid. Cancer Detect Prev  2005;29(3):276-285. 15936596
  20. Huang, R. C., Chang, C. C., and Mold, D. Survivin-dependent and -independent pathways and the induction of cancer cell death by tetra-O-methyl nordihydroguaiaretic acid. Semin Oncol 2006;33(4):479-485. 16890802
  21. Chang, C. C., Liang, Y. C., Klutz, A., Hsu, C. I., Lin, C. F., Mold, D. E., Chou, T. C., Lee, Y. C., and Huang, R. C. Reversal of multidrug resistance by two nordihydroguaiaretic acid derivatives, M4N and maltose-M3N, and their use in combination with doxorubicin or paclitaxel. Cancer Chemother Pharmacol 2006;58(5):640-653. 16544145
  22. Agarwal, R., Wang, Z. Y., Bik, D. P., and Mukhtar, H. Nordihydroguaiaretic acid, an inhibitor of lipoxygenase, also inhibits cytochrome P-450-mediated monooxygenase activity in rat epidermal and hepatic microsomes. Drug Metab Dispos  1991;19(3):620-624. 1680628
  23. Abou-Gazar, H., Bedir, E., Takamatsu, S., Ferreira, D., and Khan, I. A. Antioxidant lignans from Larrea tridentata. Phytochemistry 2004;65(17):2499-2505. 15381414
  24. Remans, P. H., van Oosterhout, M., Smeets, T. J., Sanders, M., Frederiks, W. M., Reedquist, K. A., Tak, P. P., Breedveld, F. C., and van Laar, J. M. Intracellular free radical production in synovial T lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum 2005;52(7):2003-2009. 15986371
  25. Sakakibara, M, DiFeo, D Jr, Nakatani, N, Timmerman, B, and Mabry, TJ. Flavonoid methyl ethers on theexternal leaf surface of Larrea tridentata and L. divaricata. Phytochemistry 1976;15:727-731.
  26. Hyder, PW. Total phenolics, condensed tannins, and nordihydroguaiaretic acid (NDGA) as potential allelopathic compounds in creosote bush and tarbush in the northern Chihuahuan desert. 2001;
  27. Downum, KR, Dole, J, and Rodriguez, E. Nordihydroguaiaretic acid: inter- and intrapopulational variation in the Sonoran Desert creosote bush (Larrea tridentata, Zygophyllaceae). Biochem Syst Ecol 1988;16(6):551-555.
  28. Waller, CW and Gisvold, O. A phytochemical investigation of Larrea divaricata Cav. J Am Pharm Assoc Sci Ed 1945;34:78-81.
  29. Nakadate, T., Yamamoto, S., Aizu, E., and Kato, R. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced increase in vascular permeability in mouse skin by lipoxygenase inhibitors. Jpn J Pharmacol 1985;38(2):161-168. 3928951
  30. Salari, H., Braquet, P., and Borgeat, P. Comparative effects of indomethacin, acetylenic acids, 15-HETE, nordihydroguaiaretic acid and BW755C on the metabolism of arachidonic acid in human leukocytes and platelets. Prostaglandins Leukot Med 1984;13(1):53-60. 6424136
  31. Park, R., Chang, C. C., Liang, Y. C., Chung, Y., Henry, R. A., Lin, E., Mold, D. E., and Huang, R. C. Systemic treatment with tetra-O-methyl nordihydroguaiaretic acid suppresses the growth of human xenograft tumors. Clin Cancer Res 6-15-2005;11(12):4601-4609. 15958646
  32. Arasaki, K., Tani, K., Yoshimori, T., Stephens, D. J., and Tagaya, M. Nordihydroguaiaretic acid affects multiple dynein-dynactin functions in interphase and mitotic cells. Mol Pharmacol 2007;71(2):454-460. 17105871
  33. Tian, W. X. Inhibition of fatty acid synthase by polyphenols. Curr Med Chem 2006;13(8):967-977. 16611078
  34. Lambert, JD, Meyers, RO, Timmermann, BN, and Dorr, RT. Pharmacokinetic analysis by highperformance liquid chromatography of intravenous nordihydroguaiaretic acid in the mouse. J Chromatogr B Biomed Sci Appl 2001;754(1):85-90.




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