Silybum marianum

This plant, syn. Carduus marianus (Compositae) is one of the milk-thistles. Indigenous to the Mediterranean region, it has been introduced to most areas of Europe, North and South America and Southern Australia. In addition to cultivation as a medicinal crop the plant is grown as an annual or biennial for its attractive foliage. The glabrous leaves are dark green, oblong sinuate-lobed or pinnatifid, with spiny margins. White veins give the leaves, which initially form a flat rosette, a diffusely mottled appearance. The terminal heads which appear from July to September are also spiny with deep violet and slightly fragrant flowers. The achenes, 6–7 mm in length and transversely wrinkled, are dark in colour, grey-flecked with a yellow ring near the apex. Attached to the achene is a long white pappus.

G. Ram et al. (Fitoterapia, 2005, 76, 143) studied 15 accessions of the plant and suggest that an improved crop (seed yield/plant, number of capsules/plant) could be obtained by direct selection.

As a bitter the milk-thistle has a long history but more recently it has become recognized in Germany and continental Europe as a most effective liver remedy, particularly in those forms of hepatitis affecting the liver parenchyma.

Milk-thistle fruit

BP/EP, BHP 1996 consists of the mature fruit, devoid of pappus, of Silybum marianum L. Gaertner. Several so-called flavanolignans with marked hepatoprotective properties have been isolated from the fruits. A mixture of these, termed silymarin, is available commercially as a dried, purified and standarized extract. Principal components of the extract are three pairs of diastereoisomers: silybin (silibinin) A and silybin (silibinin) B, isosilybin (isosilibinin) A and isosilybin (isosilibinin) B and, silychristin (silicristin) and silychristin (silicristin) B; see Fig. 29.2 for formulae. Other related constituents are silandrin, 3-deoxysilychristin, silymonin and silydianin. A new compound, silyamandin, has recently been isolated from incubated tincture of milk thistle; it may arise from the degradation of silydianin (Fig. 29.2) (S. L. Mackinnon et al., Planta Medica, 2007, 73, 1214). The literature nomenclature for these compounds can be confusing as recommended international proprietary names (in brackets above) may also be used and both nomenclatures still appear to be used by authors. For isolation and structural reports on the above see DY-W. Lee and Y. Liu, J. Nat. Prod., 2003, 66, 1171, 1632; W. A. Smith et al., Planta Med., 2005, 71, 877. The levels of these flavonolignans vary markedly in samples of S. marianum from different sources; they are formed by various couplings of the flavonoid taxifolin and the lignan precursor coniferyl alcohol. Silymarin, in addition to the above flavonolignans, contains 20–30% of polyphenolic compounds. The scavenging (antioxidant) properties of the silymarin components have been tested against phenylglyoxylic ketyl radicals (F. Sersen et al., Fitoterapia, 2006, 77, 525).

Fig. 29.2 Constituents of milk-thistle fruit.

Other non-specific constituents reported for the fruits involve flavonoids including taxifolin, sterols, dehydrodiconiferyl alcohol and fixed oil based principally on linoleic and oleic acids.

Silybin-like metabolites have been isolated from cell suspension cultures and although, to date, no glycosides of silybin have been reported in the plant, silybin-7-O-β-D-glucopyranoside can be produced by cell cultures of Papaver somniferum var. setigerum with added silybin (V. Kren et al., Phytochemistry, 1998, 47, 217.

The BP/EP test for milk-thistle fruit identifies silybin, silychristin and taxifolin and the liquid chromatography assay involves separation of the flavonolignans, summation of their peak areas and calculation of their total content in the drug by use of a reference solution of the same constituents; absorbance measurements are made at 282 nm.

Apart from the established use of silymarin as an antihepatotoxic agent, recent research together with clinical studies, have shown the flavonolignans to have anticancer properties (see Chapter 27).

For a 1995 extensive review of the drug (211 refs) see P. Morazzoni and E. Bombardelli, Fitoterapia, 1995, 66, 3.

Cynaria scolymus (Asteraceae/Compositae)

The leaves of the globe artichoke have been described in Chapter 19, the drug being used principally as a cholagogue (stimulation of bile production in the liver and promotion of emptying of the gall bladder and bile ducts). There has been more recent interest in the hepatoprotective properties of the plant and significant antioxidative activity has been demonstrated involving chlorogenic acid and cynarin; other constituents are, however, also implicated. For further details and references, see J. Barnes et al., Herbal Medicines, 3rd ed., 2007, p. 67. Pharmaceutical Press, London.

Peumus boldus

Boldo leaves (BP/EP; BHP 1996) are collected from the small tree Peumus boldus Molina (Monimiaceae) indigenous to Chile. The leaves are up to about 8 cm long, of coriaceous texture with a strong camphoraceous lemony odour owing to the presence of volatile oil (2%) containing ascaridole, linalool, p-cymene and cineole. E. Miraldi et al. (Fitoterapia, 1996, 67, 227) identified 46 components of the oil, 22 of which were recorded for the first time in P. boldus. The active constituents have been shown by laboratory testing to be alkaloids of the aporphine type (1–3%) the chief of which is boldine (Fig. 29.1).Boldine is reported to be a potent scavenger of hydroxyl, lipid and alkyl peroxyl radicals and experimental evidence supports its cytoprotective and anti-inflammatory properties (M. Gotteland et al., Planta Medica, 1997, 63, 311).

Studies on the genetic variation of the essential oil and alkaloid composition of the drug (H. Vogel et al., Planta Medica, 1999, 65, 90) indicated no significant differences in boldine concentration in samples from North, Central and South Chile; highest values for ascaridole were in northern collections and for p-cymene in the southern ones. There appeared to be considerable potential for the selection of superior strains. The BP requirement for volatile oil is not more than 2.0% (whole drug) and 1.5% (fragmented drug), and for alkaloid content (as boldine), not less than 0.1%. Reticuline and flavonoid glycosides have also been recorded. The bark, which contains a higher content of alkaloids (6–10%), is exported from Chile for the commercial production of boldine.

The leaves have a stimulant action on the liver and diuretic properties. An extract of the total alkaloids has a greater activity than boldine itself. The drug is also used in proprietary slimming preparations.

Taraxacum officinale root (Compositae). Syn: Dandelion root

Although now obsolete as a drug in the allopathic system of medicine dandelion root has maintained its importance in herbal medicine in which it is used as a hepatic stimulant, diuretic, tonic and antirheumatic. Commercial supplies of the cultivated drug come principally from Eastern Europe.

The drug consists of the dried vertical rhizome and tap-root which pass imperceptibly into one another. Up to 30 cm long when fresh and2.5 cm diameter, it is frequently branched with an apical crown bearing brownish hairs. The rhizome has a ring of vascular bundles and a pith; the root has a central yellow wood. Concentric zones of latex vessels occur in the thick bark. Dandelion root contains up to 25% of inulin and other polysaccharides, sesquiterpene lactones including taraxacoside, triterpenes including taraxerol, taraxol and B-amyrin, various acids including caffeic and p-hydroxyphenylacetic acids, and carotenoid yellow colouring matter.

In addition to its use in medicine the dandelion root is useful botanically for the demonstration of latex vessels (Fig. 42.7) and inulin (Fig. 42.1). The leaf has similar medicinal uses. Flavonoids, cinnamic acids and coumarins from different plant tissues and medicinal preparations have been recorded (C. A. Williams et al., Phytochemistry, 1996, 42, 121). For a review of the phytochemistry and pharmacology of the drug (over 90 refs + formulae), see K. Schultz et al., J. Ethnopharmacol. 2006, 107, 313.

Other drugs used to treat liver ailments as exemplified by the BHP (1983, 1991) and R. F. Weiss (1988, Herbal Medicine Ab Arcanum, Gothenberg, Sweden; Beaconsfield Publishers Ltd, Beaconsfield, UK), are listed below:

Chionanthus virginicus (Oleaceae)

Bark a cholagogue and hepatic stimulant.

Euonymus atropurpureus (Celastraceae)

Bark is used in combination with other drugs for the treatment of gall bladder and liver disorders; it is essentially a cholagogue.

Fumaria officinalis (Fumariaceae), syn. Common fumitory

The whole herb, which also features in a number of commercial Indian preparations, is used for liver disorders; it contains isoquinoline alkaloids including canadine, dicentrine, fumaricine and sanguinarine.

Hydrastis canadensis (Ranunculaceae)

The root is employed in atonic dyspepsia with hepatic symptoms. A fuller description of the drug is given in Chapter 26.

Iris versicolor and Iris caroliniana (Iridaceae), syn. Blue flag

The rhizome is used for biliousness with liver dysfunction.

Juglans cinerea (Juglandaceae), syn. White walnut, Butternut

The inner bark contains naphthoquinones including juglone together with fixed oil, volatile oil and tannins. Extracts are used for various conditions including use as a cholagogue.

Veronicastrum virginicum (Scrophulariaceae), syn. Black root

Used as a cholagogue.

The bulk of modern research into the testing of plant antihepatotoxic drugs has focused on those that are used in the Asian and Oriental systems of medicine in which these medicines have an important role. On the Indian market there are available many patent polyherbal preparations involving a variety of combinations of Indian herbs (for details of the components of these preparations see A. Sharma et al., Fitoterapia, 1991, 62, 229). In many instances the liver protective properties ascribed to these long-established drugs have been corroborated by clinical and animal testing. For this group of drugs more modern work appears to have been reported on the Asian and Oriental drugs than on the corresponding plants used in the traditional European system. Research from other geographical areas is now appearing in the literature. A few notes on those which have received considerable attention are given below.

Andrographis paniculata (Acanthaceae)

This plant is found throughout the plains of India and all parts have been extensively used in Unani and Ayurvedic medicine; it is also utilized in Chinese medicine. The leaf juice is a household remedy for many ailments of the alimentary tract. Sharma et al. (loc. cit.) find this plant to be one of the most active ingredients of the Indian polyherbal preparations used to treat liver ailments. A number of researchers have described the isolation of flavonoids, xanthones, sesquiterpenes, lactones and other groups of compound from the plant. (M. K. Reddy et al., Phytochemistry, 2003, 62, 1271; V. K. Dua et al., J. Ethnopharmacol., 2004, 95, 247; W. Li et al., Chem. Pharm. Bull., 2007, 55, 455). More than 20 diterpenoids and not less than 10 flavonoids are known). The active antihepatotoxic principle is probably the diterpene lactone andrographolide (Fig. 29.1), which has been shown to protect against alcohol- and carbon tetrachloride-induced hepatic microsomal lipid peroxidation. For a report on the antiallergic activity of andrographolide and neoandrographolide see P. P. Gupta et al., Pharm. Biol., 1998, 36, 72. In a systematic review of the safety and efficacy of the drug for the treatment of uncomplicated upper respiratory tract infections, J. T. Coon and E. Ernst record adverse effects as mild and infrequent with preliminary evidence for a protective effect for the above condition (Planta Medica, 2004, 70, 293).

Aralia elata (Araliaceae)

A Japanese patent (Chem. Abs., 1991, 115, 132150) exists for the isolation from this plant of pentacyclic triterpenoid saponins for the treatment of liver disorders.

Boerhavia diffusa (Nyctaginaceae)

A plant with uses in the Ayurvedic system, including the treatment of jaundice; recently, it has also been shown to be a source of phytoecdysones. A number of pharmacological actions have been demonstrated for plant extracts including inhibition of increased serum aminotransferase activity in arthritic animals and an increase in liver ATP phosphohydrolase activity. A study on the whole-plant extract indicated hepatoprotective activity in CCl₄-induced hepatotoxicity in rats; the extract is considered to be a safe and potent antihepatotoxic. A number of compounds have been isolated from the roots and hepatoprotective properties demonstrated; the most active roots were those collected in May (Lucknow) (A. K. S. Rawat et al., J. Ethnopharm., 1997, 56, 61).

Bupleurum falcatum roots (Umbelliferae)

This is one of the most important drugs in kampo, the traditional medicine of Japan, and in Chinese medicine. It is used for the treatment of chronic hepatitis, nephrosis syndrome and auto-immune diseases. A kampo formula which has shown promise in clinical trials for the treatment of chronic hepatitis B infection consists of a mixture of Bupleurum falcatum, licorice roots, Panax ginseng, Scutellaria baicalensis, Zizyphus jujuba, ginger root and Pinellia ternata (R. Reichert, Quart. Rev. Nat. Med., 1997 (Summer), 103; thro’ HerbalGram, 1998, No 43, 20).

The roots contain a group of oleanene saponins called saikosaponins a, b_1–4, c, d and f (Fig. 29.1) and in addition a coumarin, several flavonoid derivatives, polyacetylenes, and other common constituents. Minor components include three saikogenins, two polyhydroxy sterols, a trihydroxy fatty acid, a lignan and a simple chromone designated saikochromone. The total pharmacological activity of the roots is not entirely accounted for by the saikosaponin content and H. Yamanda et al. (Planta Med., 1991, 57, 555) have pointed out that the root polysaccharides have a potent antiulcer effect against HCl/ethanol-induced ulcerogenesis in mice.

Saikosaponins a and d are more active on the liver enzymes than b₁, b₂ and c. The former pair also have the stronger haemolytic and anti-inflammatory properties. Hashimoto et al. (Planta Med., 1985,51, 401) have shown that the saikosaponins enhance the activity of low doses of corticosterone with respect to the induction of liver tyrosine aminotransferase. (For summaries of the pharmacological effects, see the above paper and K. Ohuchi et al., Planta Med., 1985, 51, 208.)

Saikosaponins have been produced by cell culture and by root culture; in the former, the dried cells are recorded as containing 0.26% saikosaponin d, similar to that found in the normal roots and in the latter this saponin occurred in high concentrations in 3-month-old adventitious roots derived from callus.

In experiments in which plants were cultivated from seven collections of seeds from different habitats in Japan it was shown that the species was polymorphic with respect to the saikosaponin contents of the roots.

It appears that a number of drugs are sold on the Far East markets under the name Bupleurum Root. For Taiwanese material Bupleurum falcatum contains the highest saikosaponin content followed by the indigenous B. kaoi.

For further information on the botany, cultivation, chemistry, pharmacology, clinical applications and patents for plants of the genus see S.-L. Pan (ed.), R. Hardman (series ed.) 2006 Traditional Herbal medicines for Modern Times (Vol 7): Bupleurium Species. CRC Press/Taylor and Francis Group, Boca Raton, Fl.

Eclipta alba (Compositae)

This species is a common annual weed found throughout India and elsewhere at altitudes up to 2000 m. In India it is a common component of polyherbal mixtures used for the treatment of liver disorders. The juice of the leaves is used as a hepatic tonic and deobstruent. The herb is reported to contain an alkaloid principle (ecliptine), lactones (e.g. wedelolactone) and resin. DNA-damaging steroidal alkaloids have been reported in material obtained from the Surinam rain forest (M. S. Abdel-Kader et al., J. Nat. Prod., 1998, 61, 1202).

Opuntia fuliginosa, prickly pear cactus (Cactaceae)

This cactus is used traditionally in Mexico for the treatment of oral diabetes mellitus. Research has demonstrated its value for human subjects and a purified extract, precluding a dominant role for dietary fibre, can achieve control of experimentally induced diabetes in rats. The active constituent(s) have not been identified. (A. Trejo-González et al., J. Ethnopharm., 1996, 55, 27).

Picrorrhiza kurroa (Scrophulariaceae)

There are two species only of this genus, both perennial herbs and found in the North-western Himalayan region at 3000–4000 m. P. kurroa rhizome (kutaki in Hindi) is used for liver ailments and as a cholagogue in Indian remedies. In 1965 clinical studies on the drug by Chaturvedi and colleagues indicated that, in patients with infective hepatitis and jaundice, there was a rapid fall in serum bilirubin levels towards the normal range and a quicker recovery with no untoward effects. In 1969 extracts of P. kurroa were shown to exert hepatoprotective activity in rats against CCl₄-induced toxicity and in 1971 a hydrocholagogue activity was demonstrated. As indicated by the references given below the drug is still under intensive investigation.

The rhizome contains iridoid glycosides which have been named picroside I, picroside II, kutkoside (Fig. 29.1) and pikoroside. Various mixtures of these glycosides have been shown to possess hepato-protective properties. For references to the above and reports on the protective action of ‘Picroliv’ (a product containing about 60% picroside I and kutkoside, 1:1.5) against hepatotoxic agents see R. A. Asari et al., J. Ethnopharm., 1991, 34, 61; P. K. S. Visen et al., Phytotherapy Res., 1991, 5, 224; S. Srivastava et al., Fitoterapia, 1996, 67, 252; Qi Jia et al., J. Nat. Prod., 1999, 62, 901; R. Ananden and T. Devaki, Fitoterapia, 1999, 70, 54; K. L. Joy and R. Kuttan, J. Ethnopharm., 1999, 67, 143; B. Saraswat et al., J. Ethnopharm., 1999, 66, 263. A US patent exists for the extraction of these pharmacologically active compounds (Chem. Abs., 1992, 117, 220069).

Sedum sarmentosum (Crassulaceae)

A number of Sedum species have found use in Chinese medicine. In 1982 Chinese scientists reported the isolation of a new cyanogenetic glycoside, sarmentosin (Fig. 29.1), from plants of the genus; this compound significantly lowered the serum glutamic-pyruvic transaminase (SGPT) level of patients with chronic viral hepatitis. A considerable number of various megastigmanes and their glycosides based on the type of structure illustrated by sarmentol F (Fig. 29.1) have recently been reported in the whole plant (T. Morikawa et al., Chem. Pharm. Bull., 2007, 55, 435; M. Yoshikawa et al., J. Nat. Prod., 2007, 74, 575).

Schisandra chinensis (Magnoliaceae)

The fruits and seeds of this East Asian liana and other species of the genus are used in Chinese medicine to treat a chronic persistent type of hepatitis. In addition to its antihepatotoxic activity, the drug has been shown to have anticancer, antioxidant and physical performance improvement properties; clinical effectiveness has yet to be established. The active constituents are various biphenyl octenoid lignans; compounds isolated and characterized include wuweizisu C (Table 21.7), wuweizichun B, schisantherin A (Fig. 29.1), B, C and D which all produce a lowering of the level of SGPT. The structure–activity relationships of these lignans as PAF antagonists has been studied (I. S. Lee et al., Biol. Pharm. Bull., 1999, 22, 265). The herb Wu Wei Zi is becoming familiar in Western health food stores as a general tonic, being sold either singly or as a component of a mixture.

For a review of the botany, chemistry and pharmacology of Schisandra chinensis see J. L. Hancke et al., Fitoterapia, 1999, 70, 451; for an overview of Russian research and medicinal uses see A. Panossian and G. Wikman, J. Ethnopharm., 2008, 118, 183.

Other species of Schisandra recently investigated for their biologically active constituents, chiefly lignans and triterpenoids, include S. sphaerandra and S. propinqua; for a report on the Thai species S. verruculosa, and further references, see R. Wilairat et al., Pharm. Biol., 2006, 44, 411. The composition and biological activity of different extracts from S. chinensis and S. spheranthera have been studied (C. Huyke et al., Planta Medica, 2007, 73, 1116).

Turmeric

Turmeric (Curcuma) is the dried rhizome of Curcuma longa (Zingiberaceae), cultivated in India, West Pakistan, China and Malaya. The primary and secondary rhizomes are dug up, steamed or boiled, and dried.

The primary rhizomes are ovate or pear-shaped and are known as ‘bulb’ or ‘round’ turmeric, while the more cylindrical secondary, lateral rhizomes are about 4–7 cm long and 1–1.5 cm wide. The latter are known as ‘fingers’ and contain more yellow colouring matter than the bulb variety. Turmeric has an aromatic odour and a warm somewhat bitter taste.

Turmeric contains about 5% of diaryl heptanoid colouring materials known as curcuminoids, the chief of which is curcumin (diferuloylmethane), together with smaller quantities of dicaffeoylmethane and caffeoylferuloylmethane (Fig. 29.1). Dihydrocurcumin was reported in 1980. The volatile oil (about 5%) contains sesquiterpenes (e.g. zingiberene, 25%), sesquiterpene alcohols and ketones, and monoterpenes. A detailed study of the distribution of components of the oil in various organs of the plant has been reported (R. P. Bansal et al., Pharm. Biol., 2002, 40, 384). Enzymes associated with the biosynthesis of curcuminoids in turmeric and ginerols in ginger have been identified (M. del C. Ramirez-Ahumada et al., Phytochemistry, 2006, 67, 2017).

In a series of papers Japanese workers reported on the characterization of the constituents of a polysaccharide fraction of the drug, which has a marked immunological activity. The acid glycans designated ukonan A, B and C show remarkable reticuloendothelial system (RES) potentiating properties. Ukonan A, for example, is composed of L-arabinose, D-xylose, D-galactose, D-glucose, L-rhamnose and D-galacturonic acid in addition to small amounts of peptide moieties. Ukonan D, a neutral polysaccharide, also shows RES-potentiating activity as indicated in a carbon clearance test; it has an estimated molecular mass of 28 000 and is composed of L-arabinose, D-galactose, D-glucose and D-mannose in the molar ratio 1:1:12:0.2, plus a small peptide fraction. (For further details and references concerning these polysaccharides see R. Gonda et al., Chem. Pharm. Bull., 1992, 40, 185.)

The rhizomes also contain free arabinose (about 1.0%), fructose (12%) and glucose (2%). Abundant zingiberaceous starch grains, about 30–60 μm long and often gelatinized, are present.

Turmeric is used in Indian and Oriental medicine as an aromatic stomachic and diuretic as well as a treatment for jaundice and hepatitis. The choleretic activity of curcumin was described in 1956–7 and in vitro experiments have now demonstrated the strong antihepatotoxic action of the curcuminoids. For a review of the pharmacology of the drug see H. P. T. Ammom and M. A. Wahl, Planta Med., 1991, 57, 1.

Large quantities of turmeric are used in the preparation of curries and sauces. Paper impregnated with an alcoholic extract of turmeric is used as a test for boric acid and borates.

Javanese turmeric

The rhizome of this plant, Curcuma xanthorrhiza, is described in the BP/EP. As the name implies it is obtained from Indonesia with smaller quantities coming from India. Its constituents are similar in chemical nature and pharmacological properties to those of C. longa.

The official requirement for volatile oil content is not less than 5%, one sesquiterpene component (xanthorrhizol) being characteristic for the species. Dicinnamoyl methane derivatives (0.1%), expressed as curcumin, are assayed by absorbance measurement at 530 nm.

Curcuma zedoaria rhizome (zedoary) finds medicinal use in the East as a carminative and digestive stimulant and in the treatment of colds and infections. It occurs as circular slices of rhizome resembling bulb turmeric and contains many types of sesquiterpenoids. An active curcuminoid, demethoxycurcumin, has been isolated by bioassay-directed fractionation (W.-J. Syn et al., J. Nat. Prod., 1998, 61, 1531). The antimicrobial properties of both C. zedoaria and C. malanarica have been demonstrated (B. Wilson et al., J. Ethnopharmacol., 2005, 99, 147).

C. wenyujin is a Chinese medicinal plant, the constituents of which exhibit antitumour activity. Among other constituents the essential oil contains a novel superoxidized sesquiterpene named wenjine.

Wendelia calendulaceae (Compositae)

This herb is ascribed medicinal properties similar to those of Eclipta spp, and may be used as a single plant remedy in Asian medicine. An alcoholic extract of the plant has been shown to possess hepatoprotective activity.

Other plants for which positive antihepatotoxic properties have been recorded include: Aeginetia indica (Orobanchaceae); Artemesia capillaris buds, A. maritima (Compositae); Atractylodes sp., rhizome (Compositae); Berberis spp. (Berberidaceae); Citrus limon fruits (Rutaceae); Glycyrrhiza spp. (Leguminosae), principally glycyrrhetinic acid and glycyrrhizin (q.v.); Mallotus japonicus (Euphorbiaceae); Panax ginseng roots (Araliaceae) (q.v.); Phyllanthus niruri (Euphorbiaceae); Plumbago zeylanica (Plumbaginaceae); Salvia plebeia (Labiatae); Swertia japonica (Gentianaceae); Tephrosia purpurea (Leguminosae); Tetrapanax papyriferum leaves (Araliaceae); Uncaria gambir (Rubiaceae); Withania somnifera (Solanaceae).

There is obviously much further scope for the clinical testing of these drugs to ascertain whether toxicity levels and side-effects of the constituents would permit them to be recognized in Western medicine.