Chaparral

Scientific Name(s): Larrea divaricata Cav, Larrea tridentata (DC) Coville. Family: Zygophyllaceae

Common Name(s): Chaparral , creosote bush , greasewood , hediondilla (“little smelly one”), 1 , 2 gobernadora (“governess”) , jarilla , jarilla hembra 2 , 3 , 4

Uses

Chaparral has been traditionally used for the treatment of cancer, acne, rheumatism, and diabetes. It has also been promoted for its antioxidant effects by inhibiting free radicals. 5 Chaparral has also been used as a blood purifier and a weight loss agent. 6 However, clinical trials are lacking to support any of these uses.

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Dosing

Because chaparral has been documented as hepatotoxic at doses of crude herb from 1.5 to 3.5 g/day, its use is discouraged.

Contraindications

Chaparral was removed from the US Food and Drug Administration's Generally Recognized as Safe (GRAS) list in 1968. Increased risk for hepatotoxicity is expected in patients with hepatic dysfunction. 5 Chaparral is not recommended for use in patients with renal dysfunction due to a risk for accumulation of chaparral and toxicity. 7

Pregnancy/Lactation

Documented adverse effects (uterine activity, hepatotoxic). Avoid use. 8

Interactions

None well documented.

Adverse Reactions

The creosote bush can induce contact dermatitis. 9

Toxicology

Chaparral may cause liver damage, stimulate some malignancies, and cause contact dermatitis.

Botany

The term “chaparral” refers to an area where plants adapt to droughts, sun exposure, and fire; however, Larrea tridentata is a xerophyte (or dry land plant) that does not usually grow in the chaparral. 2 The chaparrals are a group of closely related wild shrubs found in the desert regions of the southwestern United States and northern Mexico as well as in the arid regions of South America, such as Argentina and Bolivia. 10 Chaparral products found in health food stores usually consist of leaflets and twigs. The branched bush grows up to 2 to 6 m, with small, dark-green leaves (turning a bright green after rain), and a resinous feel. 2 , 10 The leaves emit a strong odor and have a sour taste. 10 Its yellow flowers grow into white, fuzzy 5-seeded capsules. 2 The greasy resin serves as a protective mechanism against herbivores, UV radiation, and water loss in arid conditions. 10

History

Chaparral tea has been suggested for the treatment of bronchitis and the common cold, as well as for alleviating rheumatic pain, stomach pain, chicken pox, and snake bite pain. American Indians used chaparral for arthritis, bowel cramps, flatulence, colds, and chronic skin disorders. 11 Chaparral has been used internally to treat dyspepsia, dysmenorrhea, premenstrual syndrome, diabetes, gall bladder and kidney stones, dysentery, urinary tract infections, and upper respiratory tract infections. Topical applications have been promoted for rheumatic and autoimmune conditions, arthritis, back pain, minor wounds, and skin infections such as impetigo and gingivitis. 2 , 10 , 12 Chaparral has also been used as a deodorizer applied to the feet and armpits. 2 A strong tea from the leaves has been mixed with oil as a burn salve. 13 It is an ingredient in some nonprescription weight loss teas.

In 1943, chaparral was approved by the Meat Inspection Division of the US War Food Administration as a food antioxidant. It was used as a fat and butter preservative until better preservatives were introduced and its removal from the FDA's GRAS list. 10

In 1959, the National Cancer Institute received reports that several cancer patients claimed beneficial effects from drinking chaparral tea. Years later, a similar treatment was brought to the attention of physicians at the University of Utah.

Reports subsequently appeared in the lay literature describing the virtues of chaparral tea as an antineoplastic treatment.

Chemistry

The resin covering the chaparral leaves is a source of 19 flavonoids, essential oils, halogenic alkaloids, and most notably, nordihydroguaiaretic acid (NDGA) and other related lignans including nor-isoguaiasin, dihydroguaiaretic acid, partially demethylated dihydroguaiaretic acid, and 3'-demethoxyisoguaiasin. 10 , 14 The lignans are believed to exert antioxidant and antimicrobial effects. They inhibit electron chain transport in cell mitochondria, phospholipase A 2 , cyclooxygenase, and lipoxygenase. 2 NDGA is also known as masoprocol. Five to ten percent of the dry weight of the leaves is due to NDGA, which equals approximately 80% of all phenolics in the resin. 10

Uses and Pharmacology

Anticancer effects

NDGA, found in the leaves and bark of chaparral, is believed to be responsible for the biological activity of chaparral. 11 It is theorized that any anticancer effect of chaparral tea is due to the ability of NDGA to block cellular respiration. NDGA and related compounds inhibit beef heart mitochondrial nicotinamide adenine dinucleotide oxidase and succinoxidase and, therefore, exert some antioxidant activity at the cellular level. 15 Additionally, NDGA inhibits enzymes, such as receptor tyrosine kinases, that are often overexpressed in certain cancers. 10 NDGA has shown activity in breast, prostate, lung, esophageal, and skin cancers as demonstrated in cell cultures and animal models. 10 , 16

A semisynthetic derivative of NDGA, tetra-O-methyl NDGA (M4N) or terameprocol, is currently in clinical trials for the treatment of cancer. 10 This compound inhibits specificity protein 1 (Sp1)-regulated proteins to potentially block the cell cycle, cause apoptosis, and reduce angiogenesis. 17

In vitro data

NDGA was found to inhibit 5-lipoxygenase activity in an adenocarcinoma cell line. Additionally, the compound inhibited non–small cell lung cancer (NSCLC) growth and reduced colony numbers.

The anticancer effects of a crude extract containing L. tridentata were assessed in invasive breast cancer cell lines. L. tridentata was found to inhibit the growth of MCF-7/AZ breast cancer cells as well as decrease the phosphorylation levels of extracellular signal-regulated kinase (ERK) 1 and 2. MCF-7/AZ cells exposed to 180 mcg/mL of L. tridentata demonstrated a 30% decrease in cell proliferation. 18 In another study of tumoral MCF7 cells, methanolic and methane dichloride extracts of Larrea divaricata Cav. were found to exhibit a cytotoxic effect against the cell line, reducing viability. No cytotoxicity was observed for the aqueous extract. 19

A study demonstrated that NDGA was able to promote apoptosis in HER2-overexpressing breast cancer cells. This effect was noted in both trastuzumab-naive and trastuzumab-refractory cells. Coadministration of trastuzumab and NDGA was found to exert greater antiproliferative effects and a greater reduction in the survival of trastutzumab-refractory cells compared with either agent alone. 20

Animal data

NDGA inhibits the induction of the lipoxygenase inhibitor ornithine decarboxylase in mice. 21 , 22

In vitro, NDGA inhibits cancer cell growth. 23 However, it is almost completely inactive in vivo. Chaparral failed to show any significant anticancer activity in 2 tests in mice. 14 When combined with ascorbic acid, NDGA showed modest inhibitory effects against small Ehrlich ascites tumors in mice.

NSCLC xenograph growth in rats was reduced with NDGA treatment. 16

L. divaricata Cav. was found to exert antiproliferative effects and induce apoptosis on a lymphoma cell line. The compound increased hydrogen peroxide as part of its antiproliferative effects, and the authors suggested that increasing hydrogen peroxide is a novel strategy for the treatment of cancer given that low levels of hydrogen peroxide allow for proliferation. 24

Clinical data

Data from 34 cancer patients treated for varying periods of time with chaparral suggest that some malignancies are stimulated by NDGA, while some regress. 14

Antimicrobial effects

NDGA appears to be responsible for exerting antimicrobial effects. 3 It has been shown to inhibit viruses such as HIV, HPV, herpes simplex virus, and influenza virus. 10 , 25 Other microorganisms that an ethanolic extract of L. tridentata were documented to inhibit include Microsporum canis , M. gypseum , Trichophyton tonsurans , Epidermophyton floccosum , Sporothrix schenckii , Nocardia asteroides , N. brasiliensis , Shigella dysenteriae , Yersinia enterocolitica , Listeria monocytogenes , Proteus vulgaris , and Clostridium perfringens . 26

Animal data

A study in mouse peritoneal macrophages found that both an aqueous decoction (1 to 4 mg/mL) and infusion (0.8 to 4 mg/mL) of L. divaricata Cav. decreased the viability of the cells. Additionally, macrophages that were pretreated with the decoction demonstrated an increase in the phagocytosis of zymosan and Candida albicans . 27 Another similarly designed study by the same investigators found that following incubation with 4 mg/mL of decoction, an increase in the phagocytosis of zymosan, lysosomal enzyme activity, nitric oxide production, TNF-alpha release, and expression of CD14, TLR4, and CR3 occurred. 28

Clinical data

The antimycobacterial effects of L. tridentata were assessed in strains of Mycobacterium tuberculosis that were both sensitive and resistant to antituberculosis drugs. The chloroform extract of L. tridentata was found to be active against the sensitive strain of M. tuberculosis with a minimum inhibitory concentration (MIC) of 200 mcg/mL. Additionally, L. tridentata was found to be active against rifampicin-resistant (MIC 100 to 200 mcg/mL), isoniazid-resistant (100 to 200 mcg/mL), streptomycin-resistant (100 mcg/mL), and ethambutol-resistant (100 to 200 mcg/mL) strains. 29

Another study found that cold extract, infusion, decoction, and simulated digestion of L. divaricata Cav. exerted antibacterial effects against clarithromycin and metronidazole susceptible and resistant strains of Helicobacter pylori . This inhibitory activity occurred at concentrations between 0.04 to 0.1 mg/L of L. divaricata Cav. 3

The fungitoxic activity of L. divaricata against several fungi and yeasts was assessed. Growth inhibition by L. divaricata was demonstrated against species such as Lenzites elegans , Aspergillus niger , Pycnoporus sanguineus , and Ganoderma applanatum . However, the growth of Fusarium oxysporum and Schizophyllum commune were not impacted by the compound. 4

Neurodegenerative diseases

NDGA may exert a neuroprotective role due to its antioxidant properties and inhibition of lipoxygenase. This would make it a potentially attractive treatment option in neurodegenerative conditions such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, stroke, and epilepsy. 10

Animal data

Glutamate is an excitatory neurotransmitter that must be tightly regulated because its accumulation in the synaptic cleft can lead to neuronal death. 10 NDGA has been shown to induce the uptake of glutamate in mice, as well as cause up-regulation in the levels and activity of the glutamate transporter EAAT2. 30

NDGA was able to protect rat hippocampal neurons against amyloid beta-peptide toxicity in a concentration-dependent fashion. This occurred via suppression of reactive oxygen species and calcium accumulation induced by amyloid beta-peptide. Neuronal injury and accumulation of reactive oxygen species due to iron were also prevented by NDGA. 31

When assessed in a SOD1-G93A amyotrophic lateral sclerosis mouse model, NDGA did not extend lifespan. 30

Clinical data

No clinical data are available regarding the use of chaparral for its effects on neurodegenerative diseases.

Antihyperglycemic effects

Pima Indians in the southwestern United States and Mexico and the Huichol Indians of Jalisco, Mexico, have historically used oral formulations and extracts of L. tridentata for the treatment of diabetes. 12 , 32 A hot water extract with dried leaves and stems containing approximately 30 g of plant in 750 mL of water is taken by mouth (250 mL 3 times daily). 32

Animal data

In mouse models of type 2 diabetes, oral administration of masoprocol, a compound isolated from L. tridentata (a lipoxygenase inhibitor) given at a dose of 150 mg/kg twice daily was found to gradually reduce plasma glucose concentrations, with a difference of 8.5 mmol/L (153 mg/dL) compared with controls after 12 days of treatment ( P < 0.01). No increases in insulin concentrations were noted, suggesting that the compound enhances insulin activity rather than stimulates insulin secretion. Additionally, improvements in oral glucose tolerance were noted. 12

Following injection of streptozocin, diabetic Sprague-Dawley rats were randomized to receive masoprocol 0.83 mmol/kg, metformin 0.83 mmol/kg, or vehicle twice daily for 4 days. Glucose levels decreased approximately 35% in rats treated with masoprocol compared with those receiving vehicle (14.2 ± 1.1 vs 21.7 ± 1 mmol/L; P < 0.001). This occurred independently of any effects on serum insulin concentrations. Additionally, similar reductions in glucose levels were noted with metformin (12.8 ± 0.9 mmol/L). Treatment with masoprocol lowered triglycerides by 80% compared with vehicle ( P < 0.001), which was greater than that noted with metformin therapy. 32

In nondiabetic Sprague-Dawley rats with fructose-induced hypertriglyceridemia, oral masoprocol given at doses of 10, 20, and 40 mg/kg twice daily for 8 days and 80 mg/kg for 4 days was associated with a dose-dependent reduction in triglycerides compared with the vehicle. This was also associated with a reduction in free fatty acid concentrations. 33

Clinical data

No clinical data are available regarding the use of chaparral for its glucose-lowering effects.

Effects on gallstones/kidney stones
Animal data

In hamsters, a 0.5% dry ethanolic extract of L. tridentata inhibited gallstone formation and reduced biliary cholesterol. However, a 1% dry aqueous extract did not have an impact on the frequency of gallstones or any of the biliary parameters. When assessing the elimination of gallstones, a reduction in gallstone frequency, bile cholesterol concentration in the gallbladder were decreased with the ethanolic extract of L. tridentata . 34

Clinical data

No clinical data are available regarding the use of chaparral for its effects on gallstones and kidney stones.

Anti-inflammatory effects
Animal data

In a study of rats, L. divaricata given as a methanolic extract was found to prevent gastric ulcer damage at doses between 300 and 400 mg/kg body weight. Additionally, following the induction of inflammation by subcutaneous implantation of a cotton pellet, subcutaneous methanolic extract was found to reduce granuloma formation. 35

Clinical data

No clinical data are available regarding the use of chaparral for its anti-inflammatory effects.

Other uses

NDGA inhibits collagen- and ADP-induced platelet aggregation and platelet adhesiveness in aspirin-treated patients. 36

Experimental data suggest that chaparral is able to scavenge the superoxide anion radical (O 2 -). 37 The antioxidant properties of chaparral may be attributed to 4 reducing equivalents from the 2 catechol groups of NDGA. Reactive oxygen species react with hydrogen atoms found on the phenolic hydroxyl groups. 10 NDGA's antioxidant properties may be beneficial in patients with hypercholesterolemia, atherosclerosis, diabetes, and hypertension by enhancing the production of expression of endothelial nitric oxide synthase and synthesis of endothelial nitric oxide, blocking the expression of vascular adhesion molecules, and preventing the oxidation of low-density lipoprotein. 10

NDGA was shown in mice to exert renoprotective effects against potassium dichromate-induced nephrotoxicity as measured by serum creatinine, urinary excretion of protein, N-acetyl-beta-D-glucosaminidase, and serum glutathione peroxidase activity. Additionally, NDGA ameliorated areas of the kidney with structural damage in mice having less tissue and epithelial cell damage. This protective effect is believed to be due to the antioxidant properties of NDGA. 38

NDGA has demonstrated anti-inflammatory activity. Specifically, NDGA has been shown to selectively block the activity of arachidonic acid 5-lipoxygenase to cause a reduction in prostaglandin and leukotriene production. Additionally, through inhibiting enzymes such as nicotinamide adenine dinucleotide phosphate oxidase and protein kinase C and exerting effects on mitochondria in the secretory pathway, NDGA has inhibited production of leukotriene B4, degranulation, phagocytosis, and the respiratory burst. 10

Because NDGA is able to cross link collagens, it has been assessed for its use in tissue engineering. Specifically, NDGA may be a viable source for repairing ruptured or lacerated tendons, as well as other musculoskeletal injuries. It has also shown potential in preparation of heart valve tissue scaffolds. 10

Dosage

Because chaparral has been documented as hepatotoxic at doses of crude herb from 1.5 to 3.5 g/day, its use is discouraged. 39 , 40 , 41 Chaparral tea has traditionally been prepared with 1 teaspoonful of chaparral leaves/flowers steeped in 1 pint of water for 15 minutes. Additionally, a tincture of 20 drops up to 3 times daily has been used. The toxicity of these preparations is unclear. 7

Pregnancy/Lactation

Chaparral has been reported to have abortifacient effects; however, it has been used to increase fertility. Until more information is known, avoid use in pregnant women. 2 , 8 NDGA has been shown in vitro to block the synthesis of RNA proteins and lipids by the mammary glands following prolactin stimulation in mice. Until further definitive information is available, use in breast-feeding mothers is not recommended. 7

Interactions

Because NDGA inhibits platelet aggregation, there is a potential increased risk for bleeding in patients taking concomitant anticoagulants, antiplatelet drugs, or any drugs or herbals with antiplatelet properties. An increased risk for toxicity is expected in patients taking renal or hepatotoxic medications with chaparral. An additive blood glucose lowering effect may occur in patients taking hypoglycemic medications, such as insulin or sulfonylureas. NDGA blocks the activity of CYP450-mediated monooxygenase, thus increasing the risk for toxicity from medications that are substrates of this enzyme. 7

Due to the risk for hepatotoxicity, elevations in liver function tests are likely to occur. 42

Adverse Reactions

The creosote bush can induce contact dermatitis. 9

Toxicology

Chaparral has been reported to cause hepatotoxicity, 43 possibly from the ability of NDGA to inhibit cyclooxygenase, leading to the production of pro-inflammatory mediators 11 and/or the ability of chaparral to cause phytoestrogen-induced changes in liver function. Case reports have linked the ingestion of chaparral with the development of liver damage. 39 , 40 , 43 , 44 , 45 , 46 In these cases, patients took chaparral-containing products for periods ranging from 6 weeks to years. 40 , 46 They developed liver enzyme abnormalities and/or abnormal imaging studies, which resolved following discontinuation of the plant material. One case necessitated a liver transplant. 43 Another patient was using chaparral to curb alcohol cravings and developed cholestatic hepatitis following 2 months of chaparral ingestion. The investigators speculated that a risk for hepatotoxicity associated with chaparral may be heightened in patients with alcoholism who may already have liver damage. 45 Another patient was using chaparral tablets to increase milk secretion following the childbirth. She subsequently developed acute hepatitis with permanent fibrosis still present 6 months after liver function tests normalized. 46 Hepatotoxicity occurring in patients who have ingested chaparral has ranged from mild cirrhosis to fulminant liver failure, and as mentioned previously, liver transplantation. Additionally, cholestatic hepatitis, along with elevated serum transaminases, bilirubin, and alkaline phosphatase levels, appears to be the predominant form of hepatotoxicity. 11

Hepatotoxicity may be greater with capsule and tablet forms of chaparral compared with teas containing the herb. 7 However, extraction processes into teas may alter the compound into a more toxic substance. 10 Because of the risks for hepatic and renal toxicity, chaparral was removed from the FDA's GRAS list in 1968. 7 , 8 , 47

NDGA has been found to induce mesenteric lymph node and renal lesions in rats. 39 The lethal dose 50% (LD 50 ) was determined to be 75 mg/kg following a single intraperitoneal dose in mice. 10

Ipecac (no longer available) or activated charcoal with lavage has been anecdotally recommended in case of an overdose. 7

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