Plectranthus (PROSEA)

Plant Resources of South-East Asia Introduction

List of species

Plectranthus L'Hér.

Protologue: Stirp. nov.: 84, pl. 41, 42 (1788).

Family: Labiatae

Chromosome number: x= 12, 14, 15, 16, 17; P. amboinicus: 2n= 28, 32, 34, 68, 112, P. barbatus: 2n= 28, 30, 32, 34, P. scutellarioides: 2n= 16, 24, 30, 36, 40, 48, 54, 72

Major species

• Plectranthus amboinicus (Lour.) Spreng.,
• P. barbatus Andrews,
• P. scutellarioides (L.) R.Br.

Origin and geographic distribution

Plectranthus comprises approximately 200 species and is distributed in the tropical and subtropical regions of the Old World. The greatest diversity in species is found in Africa. Several species have been introduced and cultivated outside their natural areas of distribution long ago (also in tropical America) and have naturalized, and it is sometimes very difficult or even impossible to deduce their origin. About 15 species occur in the Malesian region.

Uses

The most common medicinal uses of Plectranthus in South-East Asia are externally for healing wounds, sores, swellings, burns, insect stings, aphtha and haemorrhoids, and internally to treat asthma, bronchitis, cough, dyspepsia, diarrhoea, and as an analgesic. In the African and South American tropics, the uses in local medicine are similar. In the Ayurvedic healing system in India, Plectranthus leaves are used to treat asthma, chronic cough, strangury, calculus, gonorrhoea, piles, fever, epilepsy, heart diseases, abdominal colic, dyspepsia, respiratory problems and disorders of the nervous system such as insomnia and convulsions.

In Vanuatu, P. amboinicus and P. scutellarioides have been suggested to be useful to protect Cordia alliodora (Ruiz & Pavon) Oken plantations from Phellinus noxius attack. Planting P. scutellarioides around taro (Colocasia esculenta (L.) Schott) plantations in Samoa controlled the pests Spodoptera litura (cluster caterpillar) and Tarophagus proserpina (planthopper). The leaves of several Plectranthus species and the tuberous roots of P. barbatus are used as a spice or condiment. Forms with variegated and often purplish leaves (e.g. of P. scutellarioides) are cultivated as ornamental.

Properties

Steam distillation, hexane extraction and supercritical CO₂ extraction of P. amboinicus leaves resulted in respectively 0.5%, 6.5% and 1.5% volatile compounds. Approximately 30 components were identified, with carvacrol (50-90%) as the main constituent. In another experiment, stems and leaves yielded 0.07% of a yellow essential oil after hydrodistillation, in which over 30 different compounds have been identified, with monoterpene hydrocarbons forming the major part (53%). The major components were 3-carene (16%), γ-terpinene (12%), camphor (12%) and carvacrol (13%). The antiseptic activity of P. amboinicus has been attributed to the presence of phenolic compounds such as carvacrol in the essential oil. The essential oil has antibiotic activity against numerous gram-positive and gram-negative bacteria. Biochemical studies of the leaf extract revealed the presence of hexacosanol, β-sitosterol, oleanolic acid, betulin and other triterpenoids, whereas the flavones salvigenin, 6-methoxygenkwanin, quercetin, chrysoeriol, luteolin and apigenin, the flavanone eriodyctiol and the flavanonol taxifolin were isolated from leaves of South American origin.

In vitro tests in Burma (Myanmar) with isolated trachea, intestine and uterus segments of guinea-pigs and rats showed that P. amboinicus extracts inhibited the contractions of the smooth muscles induced by carbachol, histamine and 5-hydroxytyptamine. At its minimum inhibitory concentration as antimicrobial the extract showed toxicity in the brine shrimp bioassay.

Several abietane diterpenes have been isolated from the leaves of P. barbatus grown in Brazil, but the leaves of Kenyan plants afforded highly unsaturated rearranged abietanes, and the roots of Indian plants furnished polyhydroxylated labdane diterpenes. The steroid stigmasterol has also been isolated. P. barbatus contains several diterpenes whose basic skeleton is 11-oxo-nanoyl oxide (8,13-epoxy-labd-14-en-11-one), with forskolin as the chief constituent. Forskolin was first isolated as the active component from the ayurvedic plant P. barbatus (synonym Coleus forskohlii) by 2 separate research groups almost simultaneously. This led to some confusion in the literature on the name of this compound (forskolin or coleonol) and its absolute structure (does the 7-acetoxy group of the molecule have the β-configuration or α-configuration?). Later, the identity of the two molecules was demonstrated unambiguously to correspond to the structure given to forskolin. The compound has not been found in P. amboinicus and P. scutellarioides.

Forskolin has numerous pharmacological actions. The compound has a positive inotropic action on the myocardium, and it exerts an antihypertensive activity by decreasing peripheral vascular resistance. From animal tests it has been concluded that forskolin affects blood flow and platelet parameters favourably in cases of occlusive arterial disease and reconstructive arterial surgery. Preliminary studies in humans have shown that forskolin does indeed increase the contractility of the myocardium, without increasing oxygen consumption, and that it is a vasodilator. It also possesses bronchodilating properties, causes a substantial and lasting decrease in intra-ocular pressure, and has an immunostimulant effect. Forskolin has been demonstrated to strongly inhibit the aggregation of human platelets induced by melanoma cells, showing a potential as an agent to prevent cancer metastasis. An in vitro study involving pre-injection of mice with forskolin at a dose of 82 μg/mouse, followed by tail-vein injection of cultured B16-F10 cells, reduced tumour colonization in the lungs by more than 70%. Giving forskolin orally to alloxan diabetic rats caused 37% increase in blood glucose level compared with alloxan diabetic controls, whereas feeding it for 7 days to normal rats raised blood glucose, serum insulin, glucagon and free fatty acid levels, with a corresponding increase in glucose-6-phosphatase activity and depletion of liver glycogen. Forskolin has also shown effects on the thyroid gland (increased secretion, iodine incorporation), the adrenal glands (increased steroid genesis) and the pituitary gland (increased ACTH release).

Much research has been done on the mechanism of action. Forskolin has been found to act by activating membrane-bound adenylate cyclase to cause an increase in cellular cyclic AMP (cAMP) levels. The exact site of action is a direct activation of the catalytic unit of the enzyme. The increase of cAMP e.g. in heart muscle is known to increase its contractility (due to opening of the slow Ca²⁺ channels, thus leading to a rise in intracellular calcium). In addition, increase of cAMP in the smooth muscle causes relaxation. This mechanism is probably responsible for the cardiovascular and vascular effects of forskolin. Furthermore, cAMP acts as a second messenger in many receptor-mediated signal transduction systems, e.g. that of the β-adrenergic receptor. Several hormone receptors also regulate their actions via adenylate cyclase reactions, which accounts for many of the effects of forskolin on the hormonal system.

The compound barbatusol has been isolated from Brazilian P. barbatus plants. Given intravenously at 3 mg/kg it induced potent lowering of blood pressure associated with discrete bradycardia in rats. The cardioactive dichloromethane crude stem extract of P. barbatus yields 20-deoxocarnosol (a phenolic diterpene with an abietane skeleton) and cariocal. The alcoholic extract of P. barbatus has been found to inhibit passive cutaneous anaphylaxis in mouse and rat. The extract showed highly significant antisecretory activity against Escherichia coli enterotoxin-induced secretory responses in rabbit and guinea-pig ileal loop models. Tests with mice in Brazil showed that water extracts of P. barbatus produced mild stimulation of the central nervous system, increased intestinal movements and reduced gastric secretion, indicating an antidyspeptic activity and protective activity against gastric ulcers induced by stress. A leaf extract was found active in the in vivo test against Ehrlich's ascites tumour in mice. The diterpenoids barbatusin, cyclobutatusin and 3β-hydroxy-3-deoxybarbatusin have been isolated and identified; barbatusin was the major compound. Tumour-inhibitory tests against Lewis lung carcinoma and lymphocytic leukaemia P388 in mice indicated significant inhibitory activity for barbatusin at doses of 200 mg/kg and 400 mg/kg, respectively.

The caffeic acid ester rosmarinic acid has been isolated from P. scutellarioides. This compound, which is one of the most abundant caffeic acid esters occurring in plants, is of pharmaceutical interest because of its anti-inflammatory, antiviral, antibacterial and antioxidant properties. A mixture of 6 n-saturated hydrocarbons was isolated from P. scutellarioides leaves. The sterol mixture isolated was shown to consist of 4 sterols, with β-sitosterol and stigmasterol as major components. In tests with mice in the Philippines, the leaf juice of P. scutellarioides completely inhibited the formation of all types of tumours initiated by dimethylbenzanthracene and promoted by croton oil; 67% of the mice in the control group developed skin tumours, 50% liver tumours and 33% colon tumours. The crude extract showed antibacterial activity and inhibited the growth of Ehrlich ascites tumour cells.

A crude water extract of P. scutellarioides showed in vitro fungicidal activity against Cercospora cruenta , the pathogen of leafspot of mung bean, and against Helminthosporium spp. A crude leaf extract of P. barbatus was found to have repellent action on the larvae of the cigarette beetle (Lasioderma serricorne), whereas the oil and powder of P. amboinicus significantly protected stored maize, sorghum and mung bean seeds from the attacks of the insect pests Sitophilus zeamais, Rhizopertha dominica and Callosobruchus chinensis but reduced germination of mung bean seeds. The oil from P. amboinicus has also been found to be topically toxic to red flour beetle, common cutworm, corn weevil, lesser grain borer, black armyworm and housefly, and caused 100% mortality in young Pomacea snails at 10-20 ppm in tests in the Philippines.

Adulterations and substitutes

The phenolic acid rosmarinic acid is also found in many other Labiatae (e.g. in Orthosiphon aristatus (Blume) Miq., Rosmarinus spp. and Salvia spp.) and in Boraginaceae. Diterpenes are commonly found in Labiatae, but they have limited therapeutic applications in pure form. However, some of them have therapeutic potential, just like forskolin from P. barbatus, whereas several diterpene-containing drugs are ingredients of phytotherapeutic products or allopathic proprietary drugs. Examples are compounds or drugs from Ballota, Marrubium, Rabdosia, Salvia, Sideritis and Teucrium species.

Description

• Herbs or undershrubs, aromatic, sometimes with tuberous roots.
• Leaves opposite, simple, margin serrate, crenate or dentate, petiolate, exstipulate.
• Inflorescence a lax or dense cyme or verticillaster, arranged collectively in a terminal or axillary spurious spike, raceme or panicle, 6-many-flowered.
• Flowers bisexual, zygomorphic; calyx tubular or campanulate, straight or declinate, with 5-toothed limb, usually 2-lipped with larger and broader upper lip, but teeth sometimes subequal, often accrescent; corolla with long or short tube, decurved or straight, sometimes with a spur or angle on the upper side, limb 2-lipped with short 3-4-fid, recurved upper lip and entire or notched, boat-shaped lower lip, whitish, bluish or purplish; stamens 4, declinate, filaments free or connate at base into a sheath around the style or adnate to the corolla tube but free from each other, anther cells usually confluent; disk prominent, produced anteriorly, about as long as the ovary; ovary superior, style briefly 2-fid.
• Fruit splitting into 4 orbicular, or occasionally oblong or ovoid nutlets, these smooth, granulate or punctate, 1-seeded.

Growth and development

Plectranthus usually flowers throughout the year. P. amboinicus rarely flowers in Malesia. The flowers are insect-pollinated.

Other botanical information

Coleus is often considered as distinct from Plectranthus sensu stricto, mainly on the basis of the fused bases of the filaments. However, this is a variable and unreliable character, and in most modern treatments Coleus is considered as a synonym of Plectranthus. Solenostemon is sometimes also kept apart because of the distinctly 2-lipped calyx; however, Solenostemon is connected by intermediate structures to Plectranthus s.s. (with calyx segments about equal). Here, one large genus, Plectranthus sensu lato, including Coleus and Solenostemon has been assumed, although there is still disagreement about generic delimitation in the complex.

Ecology

Plectranthus species are usually found in open locations, on waste places, roadsides, river banks and thickets, and along cropped fields, but P. scutellarioides also occurs in shaded locations and forest vegetation. P. barbatus can more readily withstand extended periods of drought than the other species.

Propagation and planting

Plectranthus is usually propagated by stem cuttings, which root readily. Usually, cuttings of 15-20 cm long are taken from the end of young stems and planted at a spacing of 40 cm × 40 cm. Soaking P. scutellarioides cuttings in placobutrazol (up to 25 mg/l) for 1.5-3 days increased the number of roots formed, but strongly inhibited shoot growth for a period of up to 10 weeks.

In vitro production of active compounds

Cell suspension cultures of P. scutellarioides have been established, producing high amounts of rosmarinic acid. In the growth phase, the cell suspension cultures are maintained in bioreactors in modified B5-medium with 2% sucrose, and later the cell mass is diluted into a production medium consisting of a 4-5% sucrose solution, where the cells start to accumulate rosmarinic acid, but grow only slowly. Rosmarinic acid starts to accumulate at the end of the growth phase and continues for only 5 days of the culture period. The accumulation of up to 21% of the cell dry weight as rosmarinic acid makes cell suspension cultures of P. scutellarioides among the highest-producing plant cell cultures with respect to secondary product formation.

The synthetic purine derivative 1-(6-purinyl)-2,5-dimethylpyrrole has a stimulatory effect on the callus, which is pale green and fluffy and considered suitable for establishing cell suspension cultures; the stimulatory effect is better than that of kinetin. A biosynthetic pathway for rosmarinic acid has been deduced from studies of the enzymes detectable in the cell suspension cultures. Eight enzymatic activities are involved in the transformation of the precursors phenylalanine and tyrosine to the end product rosmarinic acid. Continuous permeabilization of preconditioned cells with dimethyl sulphoxide showed an effective strategy for the enhanced release of rosmarinic acid while preserving cell viability. Product release peaked at 0.5% dimethyl sulphoxide.

Sucrose has a greater stimulative effect on growth and rosmarinic acid accumulation of the culture than glucose and fructose. The rosmarinic acid content in normal growth medium with 2% sucrose is similar to the level in the whole plant (about 2.5% of the cell dry weight). Rosmarinic acid contents of about 20% of the cell dry weight have been found in suspension cultures grown in medium with 4% sucrose. Low phosphate concentrations in the medium result in an increased rosmarinic acid accumulation. Callus and suspension cultures have been cryopreserved and successfully stored for periods up to 15 months, with the best results obtained when using cells from the early growth period.

Husbandry

Most Plectranthus species are easy to cultivate. Seedlings of P. barbatus grow well when transplanted in sandy soils.

Diseases and pests

In India, P. amboinicus is recorded as a host of the root-knot nematode Meloidogyne incognita, whereas P. barbatus is highly susceptible to Meloidogyne incognita and M. javanica.

Yield

In the United States sixty P. barbatus plants grown from seed yielded 430 g of dried tuberous roots after 9 months, whereas another sixty plants grown from stem cuttings yielded 730 g of dried tuberous roots. About 2 g of forskolin was isolated from 430 g dried tuberous roots.

Genetic resources and breeding

Most Plectranthus species are widespread and common in habitats that are not at risk. All the species described here (except for P. congestus) are also commonly planted. This means they are not readily liable to genetic erosion. No selection and breeding is known of, but future work might focus on obtaining large amounts of compounds with interesting medicinal properties. Chemical studies of plant material from different regions showed considerable differences in compounds isolated, providing a basis for selection.

Several other Plectranthus species seem to be local endemics which could easily become endangered, e.g. P. kunstleri Prain in Peninsular Malaysia, P. petraeus Back. ex Adelb. and P. steenisii H. Keng in Java, and P. apoensis (Elmer) H. Keng, P. merrillii H. Keng and P. sparsiflorus (Elmer) H. Keng in the Philippines.

Prospects

Plectranthus is extremely interesting medicinally. The efficacy of many of the traditional applications is supported by modern research. Forskolin is thus an example of a new pharmacologically active natural product with a unique mode of action. It is useful not only as a tool in pharmacology but also for the development of, for example, anti-hypertensive or cardioactive drugs based on a novel mechanism of action. The antitumour, antimicrobial and anti-allergenic effects of Plectranthus compounds also deserve further attention. The wide distribution and ease of cultivation make some species ideal for commercial exploitation. Although P. barbatus is neither indigenous to nor currently planted in South-East Asia, it seems worthwhile to establish experimental plantings for this promising species in the drier regions.

The presence of β-sitosterol and stigmasterol is interesting too. The former is employed in hypercholesterolaemia, and both compounds can be used as starting material for commercial semisynthesis of steroid hormones, such as corticosterone and antifertility hormones. Generally easy to propagate, Plectranthus might be developed as a commercial source of sterols of medicinal and economic importance.

A thorough taxonomical study covering the whole genus complex on a worldwide scale is desirable.

Literature

• Garcia, L.L., Takahashi, M. & Sato, T., 1978. Phytochemical investigation of Coleus blumei Benth. II. Identification of the sterol and hydrocarbon constituents. Philippine Journal of Science 107(1-2): 95-102.
• Gupta, S., Yadava, J.N.S. & Tandon, J.S., 1993. Antisecretory antidiarrhoeal activity of Indian medicinal plants against Escherichia coli enterotoxin-induced secretion in rabbit and guinea pig ileal loop models. International Journal of Pharmacognosy 31(3): 198-204.
• Kelecom, A., 1983. Isolation, structure determination, and absolute configuration of barbatusol, a new bioactive diterpene with a rearranged abietane skeleton from the labiate Coleus barbatus. Tetrahedron 39(21): 3603-3608.
• Keng, H., 1978. Labiatae. In: van Steenis, C.G.G.J. (General editor): Flora Malesiana. Series 1, Vol. 8. Sijthoff & Noordhoff International Publishers, Alphen aan den Rijn, the Netherlands. pp. 382-394.
• Petersen, M., Szabo, E., Meinhard, J., Karwatzki, B., Gertlowski, C., Kempin, B. & Fuss, E., 1995. Biosynthesis and accumulation of rosmarinic acid in suspension cultures of Coleus blumei. Plant Cell, Tissue and Organ Culture 43(2): 89-92.
• Pino, J.A., Garcia, J. & Martinez, M.A., 1996. Comparative chemical composition of the volatiles of Coleus aromaticus by steam distillation, solvent extraction and supercritical carbon dioxide extraction. Journal of Essential Oil Research 8(4): 373-375.
• Serrame, E. & Lim-Sylianco, C.Y., 1995. Anti-tumor activity of decoctions and expressed juices from Philippine medicinal plants. Philippine Journal of Science 124(3): 275-281.
• Valdés III, L.J., Mislankar, S.G. & Paul, A.G., 1987. Coleus barbatus (C. forskohlii) (Lamiaceae) and the potential new drug forskolin (coleonol). Economic Botany 41(4): 474-483.
• Vera, R., Mondon, J.M. & Pieribattesti, J.C., 1993. Chemical composition of the essential oil and aqueous extract of Plectranthus amboinicus. Planta Medica 59(2): 182-183.
• Zelnik, R., Lavie, D., Levy, E.C., Wang, A.H.J. & Paul, I.C., 1977. Barbatusin and cyclobutatusin, two novel diterpenoids from Coleus barbatus Bentham. Tetrahedron 33(12): 1457-1467.

Selection of species

• Plectranthus amboinicus
• Plectranthus barbatus
• Plectranthus congestus
• Plectranthus scutellarioides

Authors

• Mulyati Rahayu