Academic Journal Larrea tridentata (D.C.) Coville (Chaparral or Creosote Bush)

ETHNOBOTANY AND PHYTOCHEMISTRY

Ethnomedical Uses

As in all parts of the world, the cultural tradition of the natives in what is now the south-western United States included the use of plants for medicinal purposes. Foremost among these desert plants was Larrea tridentata (D.C.) Coville, considered by some to be a 'cure-all' [ 22, 100, 105]. The conditions for which this plant was most commonly employed included genito-urinary and respiratory tract infections, inflammation of the musculoskeletal system, damage to the skin, bowel cramps, and cancer, although many other applications have been reported (see table 1)

These uses correlate with the actions that Larrea tridentata is claimed to have, as follows: antimicrobial [ 20, 49, 57, 59, 62, 70, 85, 97, 111], diuretic [ 49, 62, 70, 97, 105, 111, 118], expectorant [ 49, 59, 62, 111, 118], emetic [ 22, 53, 62, 111, 118], tonic [ 49, 111, 118], anodyne (as a poultice) [ 20, 22], anti-parasitic [ 118], carminative [ 22], and blood purifier [ 114]. Any plant relied on so heavily for such a variety of diverse uses is certainly worthy of interest and investigation. Yet L. tridentata appears in very few English-language herbals that invariably contain many indigenous American plants, and not until recently has much research been initiated.

Dosage

The traditional means of employing L. tridentata included its external use as a dusting powder, poultice, plaster, and in a bath (see table 1), as well as internal consumption of a hot water extract (tea). Amounts consumed varied from less than half a cup of decoction for menstrual cramps [ 86], to half a cup followed by another dose (if necessary) of warm decoction for emetic effect in high fevers, to one cup of cooled decoction for gas or headache from upset stomach [ 22]. One recipe calls for one tablespoon of leaves and twigs infused in one pint of boiled water to be covered and left overnight. It should not be refrigerated, nor should the surface settlement be removed. Half a cup is drunk half an hour before each meal and at bedtime [ 49]. Another recipe calls for a decoction: a handful of green branch ends are boiled in 1-2 pints of water for 20 minutes and then strained out, and the solution is allowed to cool. One cup of this is to be taken [ 22]. Judging from this, it appears that an infusion is adequate if the leaves and twigs are dried (and preferably powdered), whereas a decoction may be necessary for fresh plant material that is not so easily fractured. The 'cancer tea' used in one clinical trial utilized 7-8 g of leaves per quart of water; 2-3 cups per day were consumed [ 97]. A modern alternative for those who cannot tolerate the flavour of the tea is to use tablets (size not specified): one before each meal and at bedtime [ 49]. The tincture dose is 20-30 drops, three times per day [ 71].

Classification

In its botanical context Larrea tridentata belongs to a group of unusual and important plants. It is a member of the small Caltrops family, Zygophyllaceae, whose other noteworthy members include Guaiacum officinale (L.) and Guaiacum sanctum (L.), commonly known as lignum vitae. Guaiac resin derived from these plants has been an official drug in the United States [ 3], with properties and uses similar to L. tridentata, including diuretic and antiseptic actions and indications for skin disease, rheumatism, and venereal disease [ 39, 61]. In fact, the most active constituent of Larrea, nordihydroguaiaretic acid (NDGA) (see fig. 1), was first synthesized in 1918 by reduction and demethylation of guaiaretic acid (fig. 2) from guaiac [ 62, 78]. The guaiac gum also acts as an antioxidant [ 30, 47, 56, 60], and along with NDGA was one of the first approved for this use in lard [ 47]. Research shows other shared properties with NDGA, such as antimutagenic effects and toxicity to Salmonella typhimurium and Tetrahymena pyriformis [ 15,301. The low level of toxicity of guaiac gum also closely compares with NDGA [ 21, 30, 56]. Guaiacol, like NDGA, causes inhibition of prostaglandin biosynthesis and arachidonic acid-induced platelet aggregation [ 80], making them both tools for future developments in medicine. It is safe to say that, because of these similarities, L. tridentata could be substituted for guaiacum for those conditions for which herbals recommend guaiac gum (for example, see this author's To Health With Herbs).

The genus Larrea consists of five species; two multifolate South American species growing at high elevations, L. ameghinoi and L. nitida, are significantly different from the North American L. tridenrata. Two other South American bifolate species, L. cuneifolia and L. divaricata, have greater morphological similarity to L. tridentata. L. divaricata shows the closest resemblance, as well as having a flavonoid content, phenolic thin-layer chromatogram, and protein electrophoretogram with fewer differences. In fact, there exists greater diversity within geographical variants of L. divaricata than between them and L. tridentata ploidy races. The only physical distinction between species is that the stipules of L. divaricata are obtuse, while those of L. tridentata are acuminate. The most important difference is in their chromosome number; whereas L. divaricata is diploid (n-13), L. tridentata exists as diploid (n=13), tetraploid (n=26), and hexaploid (n=39) races [ 62, 90]. For these reasons, various botanists describe L. divaricata and L. tridentata as semispecies, a vicarious species-pair, or different races [ 62, 90], subspecies [ 29], or species [ 53, 96]. This paper will assume the latter, so as to focus on the more available local species.

These (tistinctions are significant because most of the research done on the North American species identifies it as Larrea divaricata. If a reference specifically states the South American origin of the material obtained for research or analysis, it will be excluded from this paper. If of North American origin, for purposes of standardization it shall be referred to herein as Larrea tridentata, although the names (and likewise the research) are validly interchangeable.

Nomenclature

The genus Larrea was first mentioned in the literature in 1800 when Cavanilles reported the growth of Larrea divaricata in Chile. Larrea tridentata was first described in 1824 in Mexico as Zygophyllum tridentata by Decandole [ 118]. Moricaud identified it as Larrea mexicana in PI. Nouv. Amer. In his travels Fremont encountered it in the Mohave Desert and named it Zygophyllum californicum. Engelman added yet another name in 1848, L. glutinosa. Finally, the government botanist Coville gave it its official name, Larrea tridentata, in 1893 [ 59]. As if this were not enough, the German term for it was Neoschroetera tridentata (Sesse and Moc. ex D.C.) Briq. [ 18].

The common names tend to further complicate things. The most popular name, based upon use in the literature references, is creosote bush. For those who speak English, this is followed by greasewood and chaparral. The latter two, however, are undesirable because they are also applied to a variety of other western plants [ 22, 24, 49, 53, 63]. Chaparral currently seems to be the name most common among herbalists, probably because this is the term used to describe it in the controversial cancer reports [ 2, 45, 97, 98]. Another term used for it is dwarf evergreen oak [ 49]. For the Spanish speaking, the most popular names are el gobernadora and hediondilla (translated as 'little stinker' because of the musty odour it gives off, especially after a rain [ 24]). Others include hideonodo, palo ondo, gumis, falsa alcaparra, chaparro, sonora, covillea, tasajo, and jarillo. The native Americans also used several terms, including yah-temp (Paiute and Shoshone), shoegoi (Pima), and cikoi [ 22, 37, 79, 105]. The Germans use Kreosotstrauch [ 118]. Obviously, some of these are merely alternate spellings or translations, but it illustrates the difficulty of proper identification based on folk terminology.

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Distribution

One reason for the numerous names is the geographic range of the plant, which reaches beyond ethnic language boundaries. L. tridentata dominates 35 million acres [ 26], 20 million from western Texas to California in the USA [ 25]. Its range in the north is from southern California and Nevada to central Arizona and New Mexico, limited by severe winter frost or excessive winter rainfall. In the south, L. tridentata reaches to southern Baja California and northern Mexico. Its different ploidy races are prominent in the Chihuahuan (diploid), Sonoran (tetraploid), Mohave (hexaploid), and southern part of the Great Basin (hexaploid) deserts. Its range in elevation is from below sea level in Death Valley to 2,625 metres in the mountains of Mexico. It grows well on dry plains and mesas, rolling hills and slopes, and in various kinds of soil except dense, saline, or granitic types [ 53, 62, 96]. Its widespread growth in areas generally considered unproductive has led to studies of its potential commercial value. It was estimated to be a source of more than a million tons of feed and 200 million pounds of resin as an annual sustained yield (when harvested every 2-4 years) [ 26].

Description

L. tridentata is a xerophytic perennial evergreen shrub, whose individual age probably exceeds 100 years, although some clumps may survive hundreds or thousands of years through vegetative asexual reproduction. The age is determined by the size of the root crown. The root grows only about 170 cm down, but it spreads 4 m laterally. The plant size ranges from 0.5-4 m in height depending on winter or summer rain, and varies in mean height according to its ploidy race (diploid 86 cm, tetraploid 138 cm, and hexaploid 112 cm). There is no main trunk, but slender branches grow vertically or obliquely from the root crown and become dichotomous laterally [ 20, 62, 96].

The leaves are small and bifolate, dark green to yellowish green with thick cuticles and a resinous coating. They have short petioles and grow opposite on the branches, heaviest near the ends. The flowers usually appear in late winter or early spring, but may bloom anytime after a rain. Flowers grow near the ends of young shoots as solitary yellow blossoms with five petals. Though self-pollinating, the pollen and nectar attract many bees (about 30 different species). The fruits have a white hairy covering and contain five seeds, which are shed in spring and early autumn and are distributed by wind and rain run-off [ 20, 62, 96].

Germination occurs for 6-40% in the moist heat of July and August, but survival is low. This is due to a growth inhibitor that may be emitted by the roots. It not only inhibits its own seeds' germination and growth but those of other plants as well. This allelopathic activity is present in the entire plant and is not due primarily to NDGA, although this contributes its phytotoxic effect. The inhibitor is washed from the soil by the rain, after which seedlings may appear, but they die as the soil dries. Larrea thus maintains its identity as a solitary plant [ 7, 20, 28, 62, 96, 100, 118].

Constituents

Nordihydroguaiaretic acid (NDGA), chemically described as beta, gammadimethyl-alpha, delta-bis ( 3, 4-dihydroxyphenyl) butane, is certainly the most significant of the many important compounds contained in L. tridentata. It has been determined to have antioxidant, anti-inflammatory, cytotoxic, anti-microbial, and enzyme-inhibiting activity. It occurs in all species and hybrids of Larrea [ 62, 118]. There is a slight difference in mean concentration between the ploidy races as you move from the Chihuahuan Desert (2.62%) to the Sonoran (3.84%) to the Mohave (4.86%), but it appears that the concentration is independent of relative rainfall and time of year harvested [ 33]. There can be significant variations between neighbouring shrubs [ 37], with greater concentrations in young plants [ 34] and young leaves [ 62], as opposed to old plants and mature leaves. NDGA is unstable in water [ 109] and air [ 14], undergoing oxidation to an o-quinone form catalysed by the Larrea enzyme phenoloxidase as it is macerated [ 62]. The purpose of NDGA and its o-quinone derivative is evidently to repel herbivores [ 37, 50, 62], an important function since there are 30 species from five orders of insects associated with L. tridentata (as well as 26 species of spiders) [ 62]. Livestock will normally not eat Larrea [ 53, 59, 118], but willonce the resin is removed, as it is an excellent protein source, comparable to alfalfa [ 25, 26].

NDGA's concentration in the dry weight of plant parts varies from 5-10% in the leaves [ 62] to 2-6.5% in the leaves, small twigs, and flowering tops [ 33], to 1.3% in all aerial parts [ 79]. There is less than 1% in the heavy stems and branches [ 48]. It comprises about 50% of the resin that accounts for 10-15% of the dry weight of the leaves [ 90].

Although hot water was traditionally used as a solvent for Larrea, only about 40% of the available NDGA is extracted [ 97]. A 95% purified ethanol solvent used for 1.5-4 hours [ 27] is superior if maximum NDGA concentration is desired.

There is also an array of over 20 aglycone flavonoid methyl ethers that make up the other half of the resin. The 16 flavonoid glycosides that are water-soluble occur only internally in the leaves and are not found in the resinous exudate. The flavonoids are identical in all three L. tridentata ploidy races [ 62, 90]. Certain of these have some activities in common with NDGA. Apigenin has been shown to inhibit NADH oxidase [ 12]. The yellow crystals identified as a dimethoxyl morin [ 48] show cytotoxic activity [ 118]. Although quercetin has not been identified in any species of Larrea [ 62], it has seven methyl ether and two glucoside derivatives that occur in L. tridentata. It is probable that these retain some of the activity that quercetin shares with the more potent NDGA, such as inhibition of NADH oxidase [ 12], phospholipase A2 [ 55], and lipoxygenase [ 17, 76, 116].

The possible effects of all the different flavonoids and other constituents are numerous and varied. What should be noted are those with activities that differ from NDGA, yet help explain the historic uses ascribed to Larrea. The flavonoid kaempferol and the amino acid arginine are diuretic. Kaempferol also is natriuretic (increases the rate of sodium excretion in the urine) [ 114]. The most interesting activity demonstrated by certain flavonoid constituents is the anti-viral effect shown by the 3-methoxyflavones, including 3-methyl-kaempferol, 3,3'-dimethyl-quercetin, 3,7-dimethyl-quercetin, and 3,7,3'-trimethyl-quercetin. These were active against the pico RNA viruses, including polio, coxsackie B2, and rhino viruses, and also the vesicular stomatitis and bunya viruses. These substances are considered true anti-virals, since they affect the step of replication between uncoating and the initiation of RNA synthesis, are virus-specific, and are also irreversible. Since the 3-methoxy function is structurally essential for this flavone activity, eight other Larrea flavonoid constituents also potentially have this property [ 108].

The other phenolic constituents besides the flavonoids that mimic the biologic activity of the lignan NDGA include three other lignans: norisoguaiacin (fig. 3), dihydroguaiaretic acid (fig. 5), and partially demethylated dihydroguaiaretic acid (fig. 6). Norisoguaiacin demonstrated anti-microbial and antioxidant activity [ 34], as well as mitochondrial electron transport and enzyme inhibition [ 82, 93]. Dihydroguaiaretic acid showed anti-microbial properties [ 34], while partially demethylated dihydroguaiaretic acid also inhibits mitochondrial electron transport [ 46] and certain enzymes [ 93] (see tables 3 and 7).

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The combined effects of these constituents of L. tridentata suggest a synergism that enhances the effect of the primary active compound, NDGA, and indicates the advantage of using an extract of the entire leaf/twig structure as opposed to a purified NDGA preparation. There are numerous other components of L. tridentata that may further increase its therapeutic potential, as well as nutritional substances that add to its efficacy (see table 2).

BIOLOGICAL ACTIVITY OF L. TRIDENTATA AND NDGA

Antioxidant

The first scientific application of Larrea resulted from the discovery in 1942 of NDGA as a major constituent of its resinous exudate. NDGA as extracted from Larrea was used as an antioxidant from 1943 until 1973, when a commercially satisfactory synthesis became available. NDGA is one of the most effective antioxidants known [ 78]. Not only is it a hydrogen donor [ 116], but its inhibition of lipoxygenase prevents oxidation of plant oils [ 101, 102], while it protects animal fats from being oxidized by haematin compounds [ 78, 103]. The hydrogen donor effect appears dominant at lower concentrations (less than 1 x 10(-4) M), while lipoxygenase inhibition tends to dominate at higher concentrations. NDGA is also the best lipoxygenase inhibitor at low temperatures [ 102].

It is normally used in food at 0.01-0.02%, although its range in efficacy is from 0.001% (least) to 0.05% (most) [ 10, 14, 26, 47, 60, 83, 97, 99]. It is effective from pH 5 to 9 [ 78] and its effect is enhanced synergistically by vitamin C [ 60, 78] and citric acid [ 64, 83]. It increases the keeping time of foods by 2 to 8 times [ 60, 64, 99]. Though used primarily for fats and oils, it has also been used in meat, poultry and fish, dairy products, frozen foods, baking mixes and baked goods, candies, vitamins, pharmaceuticals, and even perfumery oils [ 14, 26, 47, 60, 62, 64, 78, 83, 97, 99, 102, 118]. NDGA's free radical scavenging activity has demonstrated a dramatic ability to extend the average life-span of mosquitoes by over 50% [ 1].

Anti-inflammatory/Anti-asthmatic

Studies of NDGA's lipoxygenase inhibition have shown that this action occurs in cell-free, intact cell, and tissue preparations [ 17], and it blocks the formation of inflammatory arachidonic acid products [ 110]. The resulting effects include a decrease in vascular permeability and exudation upon exposure to an inflammatory substance [ 111]. NDGA also inhibits late-phase inflammatory reaction induced by these products, the leukotrienes (LT) or hydroxy-5,8,10,14-eicosatetraenoic acids (HETE), both of which are chemotactic and increase leucocyte infiltration [ 69]. In fact, NDGA was shown to reduce formation of 5-HETE and 15-HETE [ 17], as well as 12-HETE [ 43, 67]. In so doing NDGA also effectively reduced synthesis of LT-B( 4), which is found concentrated in joints with rheumatoid arthritis, where it causes chemotaxis and degranulation of neutrophils [ 17]. This helps explain the observation that NDGA was found to be analgesic to humans in vivo [ 8]. NDGA was also shown to inhibit both allergic and non-allergic histamine secretion in several in vitro test models [ 4, 16, 72].

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Besides inhibiting the inflammatory response, NDGA's lipoxygenase inhibition blocks the release of SR-A (slow-reacting substance of anaphylaxis), also identified as LT-D, from sensitized lung tissue after an antigen challenge. Prostaglandin and histamine release were also inhibited by about 30%; the anaphylactic contractile response was measurably reduced. This duplicates the activity of diethyl carbamazine, a drug used to treat asthma; NDGA is thus implicated for future clinical research on asthma [ 4, 72, 117]. In addition, 12-HETE, the synthesis of which is inhibited by NDGA in lung tissue, is found in increased concentration in the platelets of asthmatics [ 17, 43].

The lipoxygenase products of arachidonic acid metabolism are also thought to play a central role in tumour promotion [ 113] (see next section). The useful effect of inhibiting lipoxygenase is compounded by the fact that NDGA also blocks arachidonic acid release from phospholipids by inhibiting the enzyme phospholipase A( 2) [ 55]. This mimics the activity of steroid drugs, which thereby reduce prostaglandin (PG) synthesis. Excessive PG production exacerbates the symptomatology of certain inflammatory conditions, including rheumatoid arthritis [ 85]. Other products of arachidonic acid metabolism are also blocked (some studies showing the inhibition of cyclooxygenase by NDGA [ 17, 67, 68] while others do not [ 76]). These include PGE( 2), keto-PGF( 1) alpha and PGF( 2) alpha through inhibition of prostaglandin synthetase [ 66, 80] and thromboxane (TX) B( 2) through inhibition of thromboxane synthase [ 44]. But the overall physiologic effect of these actions is difficult to predict. For example, PGE( 2) relaxes human bronchiolar smooth muscle, while PGF( 2) alpha causes it to contract. Keto-PGF( 1) alpha has little or no biological activity and TX B( 2) seems to have little physiological significance, though its blood concentration is increased during asthmatic attacks [ 85].

Various other enzyme inhibitions occur with NDGA that help explain some of its usefulness (see tables 3 and 4). This ubiquitous activity is due to the amphipathic character of the molecule, the flexibility to accommodate to a variety of binding sites, and the ability to chelate metal co-factors [ 93]. Those enzyme systems that are not affected have also been noted (see table 6). All studies, except one [ 76], were done in vitro.

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Cancer Treatment/Prevention

Much of the recent attention received by L. tridentata and NDGA has been in regard to their potential in the treatment of cancer. Larrea extracts have been found to be cytotoxic and anti-neoplastic [ 12, 118]. It has been proved that NDGA is not solely responsible for the cytotoxic activity. In vitro studies of Larrea showed cytotoxicity to Vero and Hep 2 cell lines by organic solvent extracts and to MOPC culture by the diethyl ether fraction (75.8% NDGA), as well as the yellow flavonoid crystals [ 118]. NDGA was cytotoxic in vitro to Krebs-2 ascites cells, Ehrlich ascites tumour, and L1210 mouse leukaemia cells [ 14]. It also suppressed tumour cell clone formation of mouse L and human WISH cells [ 11]. However, screening of NDGA by the Cancer Chemotherapy National Service Center in 1955, 1959, and 1969 was negative for sarcoma 180, mammary adenocarcinoma 755, and leukaemia L1210 in mice [ 97, 98].

Research showing that NDGA inhibits anaerobic respiration by blocking energy transfer and inhibits electron transport by disruption of folic acid dehydrogenase and through inhibition of mitochondrial NADH oxidase and succinoxidase [ 10, 14, 28, 81] gave a possible mechanistic explanation for the inhibition of the primary respiratory pathway of cancers. (The anti-cancer effect of podophyllotoxin, a component of another plant resin, has been shown to be proportional to its ability to inhibit tumour cell respiration [ 46].) It has also been shown histologically that changes in mitochondria and nucleoli have preceded cell death in NDGA-treated cell lines [ 118]. Furthermore, an O( 2)-mediated product of NDGA was found to form a stable complex with DNA; nucleic acid metabolic interference is a common function of anti-neoplastic agents [ 109]. Evidence was mounting to recommend further study.

But the greatest excitement was generated by the case of dramatic regression of a facial malignant melanoma in an 85-year-old man after the regular drinking of a tea made from L. tridentata [ 97]. An in vivo study with NDGA and Larrea tea followed in 104 mice with ependymoblastomas; tumour disappearance occurred in four and reduced tumour growth in two. No inhibition in 150 mice with melanoma was seen. In human clinical trials of 59 patients with advanced incurable malignancies, a variety of cancers were treated with either L. tridentata tea (two to three 8 oz doses, equivalent to 200-250 mg NDGA daily) or NDGA (250-3,000 mg/day) orally. Of 45 evaluable cases, there were only 6 regressions (2 melanomas, 2 colon cancers, 1 testicular choriocarcinoma, and 1 lymphosarcoma). There were not enough regressions of any specific cancer type for the trial to be considered effective. On the contrary, even though 27 patients reported subjective improvement, a majority seemed to undergo tumour stimulation [ 2, 98]. This may be due to the fact that cellular respiration is stimulated at low concentrations of NDGA, but inhibited at higher levels [ 92, 98]. In any case, its generalized application as a cancer therapy at this time remains controversial.

On the other hand, the usefulness of NDGA as an inhibitor of carcinogenesis may be less debatable. NDGA has been shown to inhibit chromosome breakage induced by a tumour promoter via blockage of lipoxygenase production of lipid hydroperoxides (HPETE) and aldehydes, besides acting as a radical scavenger [ 29]. It strongly inhibits the mutagenicity of benzopyrene [ 15], one of the major tumour initiators in cigarette smoke. NDGA prevents local induction of ornithine decarboxylase, which is implicated in neoplastic growth, by a tumour-promoting agent and also inhibits production of papillomas by the same substance by 82% [ 75]. NDGA use resulted in significantly fewer ( 25-40%) cases of mammary cancer after exposure to an organ-specific carcinogen, owing to reduced lipoxygenase production of LT, HETE, and HPETE, with no signs of toxicity at effective dosage levels (unlike other tumour or lipoxygenase inhibitors) [ 65]. NDGA also prevents the increase in cGMP which normally occurs when cells are stimulated by tumour promoters, and thereby acts as an anti-promoter [ 19, 112] (see table 5).

Anti-microbial

Many phenolic substances are bacteriocidal because they react chemically with sensitive enzyme systems and render them catalytically inactive [ 103]. Owing to the inhibiting effect on numerous enzyme systems, L. tridentata and NDGA have a broad spectrum of activity as antiseptic agents (see table 7). Studies comparing various extractions from L. tridentata showed that the NDGA fraction was not responsible for all the anti-microbial activity [ 34, 118]. It was also demonstrated that synthetic NDGA was less effective or ineffective against some bacteria that natural (extracted) NDGA successfully inhibited [ 118].

Disease conditions caused by the organisms inhibited include the following bacterial infections: boils, paratyphoid, anthrax, scarlet fever, nocardiosis, lobar pneumonia, wound infections, upper respiratory tract and urinary infections, and caries. Susceptible yeast and fungal organisms can cause aspergillosis, sporotrichosis, candidiasis, cryptococcosis, histoplasmosis, and blastomycosis. The effect on the organisms has only been demonstrated in vitro (except for Streptococcus pneumoniae type II in mice), so it is not fair to assume that Larrea can successfully control all the aforementioned infections. However, the research does suggest the potential for in vivo efficacy, particularly in the light of the traditional therapeutic applications by Indian tribes of the Southwest (see table 1).

Other Effects

There are numerous ongoing investigations into the possible applications of NDGA. Certain recent findings support some historical uses, while others have no apparent therapeutic significance, but primarily offer food for thought. Among some of the results obtained are claims that NDGA increases vitamin C concentration in the adrenals, and is useful in treating geriatric complaints and liver ailments due to alcoholism [ 78]. It has been shown to have vasodepressant [ 8] and CNS depressant [ 51] activity in vivo in cats. One study showed a 73-83% reduction of caries in hamsters when NDGA was consumed in water at a concentration of 0.01% [ 58], while other research showed no caries reduction in rats with 0.5% NDGA in the diet, though there was appreciable weight loss [ 52]. The form consumed may help explain the discrepancy in these results [ 14]. Insulin secretion induced by glucose, glucagon, and drugs in rat beta islet cells was reduced by NDGA concurrent with a reduction of cAMP accumulation [ 67, 68]. Also, NDGA was found to inhibit arachidonic acid-induced platelet aggregation [ 80].

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A variety of leucocytic effects occur that may help explain NDGA's usefulness in allergy and auto-immune symptomatology. Antibody production by the TI2 (thymus independent subset 2) B-lymphocyte population is inhibited [ 11]. Mitogenesis in human lymphocytes is also inhibited [ 54]. NDGA is a potent inhibitor of lysosomal enzyme release in neutrophils, and also causes a decrease in chemotactic factor-induced calcium and sodium influx [ 73]. A decrease in neotrophil phagocytosis likewise occurs due to the blockage of the arachidonic acid cascade by NDGA [ 87].

TOXICITY

Any plant with as great a bioactivity as Larrea would be expected to exhibit a significant toxicity. Yet, on the contrary, little symptomatology has been discovered with L. tridentata or NDGA. In the study of 59 terminal cancer patients taking either the tea or NDGA orally, 13 experienced nausea and vomiting (Larrea is an emetic), 9 had diarrhoea, 2 had abdominal cramps, 1 developed a rash, 1 had stomatitis and 1 ran a fever [ 98]. How many of these were directly caused by the medication is difficult to discern. Dermititis is known to occur on exposure to Larrea by allergic individuals, but only rarely [ 53]. Weight loss is found in rats with NDGA at a level of 0.5% of the diet for 90 days [ 52].

The criterion of safety for use as an antioxidant is an acute LD( 50) (lethal dose in 50%) of over 1,000 mg/kg orally. NDGA had an oral LD[ 50] of 2,000-4,000 mg/kg in mice and 2,000-5,500 mg/kg in rats [ 30, 56]. Intraperitoneally, it was 550-800 mg/kg for mice [ 56, 78, 97] and 600 mg/kg for rats [ 8]. The intravenous LD( 50) for rats is 100 mg/kg [ 8]. NDGA was thereby established as being acutely non-toxic, since toxicity is purely a function of relative dosage.

An antioxidant substance is designated as harmless in chronic exposure if a dose of 100 times the amount to be used in foods causes no significant effect on growth as measured in the first six months in the life of a rat. For NDGA, the amount tested was therefore 1%; this reduced the growth rate by 10-15% [ 56]. Another study with hamsters showed that 0.01% for 50 days had no ill effect [ 58]. But in a 17-month test in rats, 0.5-1.0% in the diet caused cystic reticuloendotheliosis of paracaecal lymph nodes and vacuolization of kidney tubular epithelium. In a shorter amount of time, a 2% concentration caused similar changes [ 38]. A 15-month study with 3% NDGA caused a cystic nephropathy [ 36]. A two-year study using 1% NDGA resulted in diminished food intake and growth in rats, as well as the formation of mesenteric cysts with caecal haemorrhages [ 21, 56].

The mechanism explaining these changes has to do with the metabolism and excretion of NDGA. NDGA is converted by several enzymes, including catechol-o-methyl transferase (COMT) to dihydroguaiaretic acid and by pyrocatechase to muconic acids [ 13]. But, most importantly, catalase causes its transformation to an o-quinone form. This occurs in the lower ileum and caecum, where it is absorbed and then filtered through the regional lymph nodes before being excreted via the urine [ 13, 38, 116]. Owing to the high concentration and reduced solubility of this form, it is postulated that it is taken up by the proximal tubular epithelium, where it accumulates in lysosomes. With coalescing of adjacent affected tubules, the formation of pseudocysts by focal histiocyte collections occurs in interstitial areas [ 36].

It is apparent that long-term exposure to inordinate concentrations of the active constituent of Larrea, NDGA, poses a hazard to those tissues that sequester its metabolites. Furthermore, a degree of weight loss or a reduction in normal growth may also occur, possibly owing to the protein-complexing properties of NDGA. But this is probably not significant outside pregnant women or nursing infants, for whom consumption of NDGA is contraindicated for other reasons as well (see below). It is highly improbable that equivalent amounts of Larrea would be consumed consistently by people. In one human study, up to 400mg/kg/day were given intramuscularly for as long as 5-6 months, showing little evidence of toxicity [ 8]. Assuming a maximum 10% NDGA concentration in Larrea leaves, for a 70 kg man this safe dosage would be 280 g or 9 oz/day of crude leaf or fluid extract. Tests for haemoglobin, white blood cell count, SGOT, BUN, bilirubin, alkaline phosphatase, and urinalysis showed no abnormalities in human patients taking from 250 to 3,000 mg NDGA/day by mouth for one year [ 97, 98].

Certain actions of NDGA suggest conditions in which its use would be contraindicated. Anyone on barbiturate medication should avoid its use, since NDGA is a weak inhibitor of the hepatic microsomal enzymes that metabolize them [ 32]. Owing to the inhibition of COMT, persons with elevated catecholamines should avoid its use [ 13]. Hypothyroid patients should not use Larrea because of the antithyrotropic activity of NDGA (80 mcg/ml caused a 50% inhibition in the binding of TSH to the thyroid plasma membrane) [ 5]. The action of NDGA blocks the stimulation by prolactin in mammary tissue of RNA, casein and lipid biosynthesis; nursing mothers should be advised to avoid it [ 84]. Finally, because the South American species, L. divaricata, has a tradition of use as an abortifacient due to its emmenogogue activity, it is contraindicated for use in early pregnancy [ 6].

SUMMARY

Larrea tridentata, known commonly as creosote bush, is the North American representative of a group of closely related plants that have been traditionally used for medicine by both native Americans and regular physicians. It is a desert shrub with high concentrations of an active constituent, nordihydroguaiaretic acid (NDGA), in the resin covering its leaves and small stems. Scientific research into NDGA's usefulness as an antioxidant, anti-inflammatory, anti-microbial, anti-tumour-promoter, and enzyme inhibitor of low toxicity supports the major medical applications for which Larrea had been previously employed. Continuing research on its influence in asthma, allergies, and auto-immune disease will, one hopes, help uncover the mysteries and further the appreciation of the tremendous potential that exists in this humble plant.
REFERENCES

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ADDENDUM. POTENTIAL TOXICITY OF LARREA TRIDENTATA

On 10 December 1992, the Food and Drug Administration (FDA), one of eight agencies of the Public Health Service within the US Department of Health and Human Services, issued a warning to the public concerning the use of Larrea tridentata, called chaparral or creosote bush. Several cases of acute toxic hepatitis have been associated with the consumption of the dried powdered leaves of this plant in tablet or capsule form. Patient histories and tests for viral or other chemical causes of hepatitis in these cases were negative [ 1].

The first report of this association was made in 1990. The incident occurred in 1983 when a 33-year-old woman consumed 15 tablets of chaparral leaf per day for three months. At that time she developed anorexia, nausea, and retrosternal pain. After another month her urine became dark. She reduced the dose to one tablet per day for several weeks and her appetite returned as the pain and dark urine disappeared. Then she increased the dose to seven tablets per day and after several weeks her nausea and pain returned. In addition she developed jaundice, oedema, and fatigue. When she discontinued the tablets completely her appetite returned but her stools became pale and the jaundice, oedema, and fatigue persisted. She was then examined and hospitalized. No liver enlargement was found but serum levels of bilirubin and liver enzymes were greatly elevated above normal. After three weeks of supportive care and diuretic therapy she was asymptomatic except for fatigue, which persisted for one year. Her serum liver enzymes gradually returned to normal [ 2].

Next, in July 1992 a 41-year-old woman developed right upper-quadrant abdominal pain and jaundice after consuming about two tablets of chaparral per day for 11 weeks (150 tablets total). She stopped chaparral use and was admitted to a hospital. Again no liver enlargement was found but serum bilirubin and liver enzyme levels were greatly increased. Her serum chemistry gradually improved and she was asymptomatic after three months. Also, in July 1992 a 42-year-old man developed jaundice after taking three 500 mg capsules of chaparral per day for six weeks. Five days after stopping its use he was examined and found to have a slightly enlarged liver and elevated serum levels of bilirubin and liver enzymes. Four weeks later he was asymptomatic and in another three weeks his serum liver enzymes were normal [ 3].

Another similar case was reported to the FDA and Center for Disease Control in November 1992. The patient again recovered after discontinuing chaparral consumption and undergoing medical treatment. But in a case reported in December 1992, a patient with preexisting liver damage became severely ill with liver and kidney failure after taking unknown quantities of chaparral. Because of these incidences the FDA has determined that ingestion of chaparral poses a potential risk to the health of the public, particularly of those with underlying liver damage. Investigations about these products and their uses are ongoing [ 1].

Prior to these cases the only published report of Larrea toxicity was a case in 1937 of contact dermatitis in a sensitive individual who gathered branches from a live chaparral shrub [ 4]. American Indians and Mexicans traditionally used the leaves to make a medicinal tea to take internally or apply externally. They used the warmed branches and leaves locally as a poultice. Since a published report on its use as a tea for cancer in 1969 the popularity of chaparral has become widespread. On the basis of a survey of four leading herbal companies conducted by the Herb Research Foundation, the amount of chaparral sold in the United States over the last 20 years is at least 200 tons. Internal consumption of the powdered leaves is apparently a modern development. Since the component that caused the toxicity in these cases of hepatitis has not been identified with certainty, the possibility exists that the products were mislabelled or adulterated or that a chemical contaminant of the chaparral leaves is responsible. Chemical contamination can come from the soil, inadvertent spraying with pesticides, fungal growth in harvested leaves, or other sources. It remains to be shown whether the toxic substance is normally present only in Larrea leaves or also in extracts of the leaves, and whether it is toxic to all, only some, or just a few sensitive individuals who consume it internally. The external application of chaparral and its extracts has not been shown to be toxic unless a person is allergic to this plant.
References

1. Stone, B. FDA news release, 10 December 1992.

2. Katz, M; Saibil, F. Herbal Hepatitis: Subacute Hepatic Necrosis Secondary to Chaparral Leaf. J. Clin. Gastroenterol., 12(2): 203-206 (1990).

3. Clark, F.; Reed, R. Chaparral-induced Toxic Hepatitis -- California and Texas, 1992. Morb. Mortal Week. Rep., 1992, pp. 812-14.

4. Smith, L.M. Dermatitis Caused by Creosote Bush. J. Allergy, 8: 187-88 (1937).

The British Journal of Phytotherapy.

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