Perilla

Scientific Name(s): Perilla frutescens (L.) Britt. Family: Lamiaceae

Common Name(s): Beefsteak plant , perilla , wild coleus , purple mint , shiso (Japanese)

Uses

Perilla leaves are used in Chinese medicine to treat a wide variety of ailments, as well as in Asian cooking as a garnish and as a possible antidote to food poisoning. Leaf extracts have shown antioxidant, antiallergic, anti-inflammatory, antidepressant, anorexigenic, and tumor-preventing properties. However, there is a lack of clinical data to support perilla for any use.

Dosing

Clinical trials are lacking to provide dosage recommendations.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Perilla oil may cause dermatitis.

Toxicology

None well documented.

Botany

Perilla is an annual herb indigenous to eastern Asia but which has become naturalized to the southeastern United States, particularly in semishaded, damp woodlands. The plant is attractive, with deep purple, square stems and reddish-purple leaves. The leaves are ovate, hairy, and petiolated, with ruffled or curly edges; some very large red leaves are reminiscent of a slice of raw beef, hence the common name of beefsteak plant. Small tubular flowers are borne on long spikes that arise from the leaf axils between July and October. The plant has a strong fragrance sometimes described as minty. 1 , 2

History

The leaves and seeds are widely eaten in Asia. In Japan, perilla leaves are used as a garnish on raw fish dishes serving the dual purposes of flavoring and as an antidote to possible food poisoning. The seeds are expressed to yield edible oil that is also used in commercial manufacturing processes for the production of varnishes, dyes, and inks. Dried leaves are used for many applications in Chinese herbal medicine, including treatment of respiratory conditions (eg, asthma, coughs, colds), as an antispasmodic, to induce sweating, to quell nausea, and to alleviate sunstroke. 2 , 3

Chemistry

Perilla leaves yield about 0.2% of a delicately fragrant essential oil that varies widely in composition and includes hydrocarbons, alcohols, aldehydes, ketones, and furan. The seeds have a fixed oil content of approximately 40%, with a large proportion of unsaturated fatty acids, mainly alpha-linoleic acid. The plant also contains pseudotannins and antioxidants typical of the mint family. An anthocyanin pigment, perillanin chloride, is responsible for the reddish-purple coloration of some cultivars. Several different chemotypes have been identified. In the most frequently cultivated chemotype, the main component is perillaldehyde, with smaller amounts of limonene, linalool, beta-caryophyllene, menthol, alpha-pinene, perillene, and elemicin. The oxime of perilla aldehyde (perillartin) is reported to be 2,000 times sweeter than sugar and is used as an artificial sweetener in Japan. Other compounds of possible commercial interest include citral, a pleasantly lemon-scented compound; rosefurane, used in the perfume industry; and simple phenylpropanoids of value to the pharmaceutical industry. Rosmarinic, ferulic, caffeic, and tormentic acids and luteolin, apigenin, and catechin have also been isolated from perilla, as well as long-chain policosanols of interest in platelet aggregation. A high myristin content renders certain chemotypes toxic; ketones, such as perilla ketone and isoegomaketone, found in others are potent pneumotoxins. High-performance liquid chromatography, gas, and thin-layer chromatography have all been used to identify chemical constituents. 2 , 4 , 5 , 6

Uses and Pharmacology

Antioxidant properties of perilla leaf and seed extracts, as well as individual chemical constituents, have been extensively studied in experimental models, 5 , 7 , 8 , 9 with limited therapeutic applications evaluated. 10 , 11 , 12 , 13 , 14

Anti-inflammatory and antiallergic effects

In vitro modeling has been used to describe anti-inflammatory properties of perilla. A marked influx of neutrophils and formation of leukotriene B4, along with changes in thromboxane B2 levels, was demonstrated in 1 experiment. In another, large increases in prostaglandin levels were seen. In a contact dermatitis model, perilla induced hypersensitivity mediated by leukotrienes, prostaglandins, histamine, inflammatory cytokines, and immunoglobulin E (IgE). 15 Extracts of perilla have also been shown to suppress the overproduction of tumor necrosis factor-alpha, a cytokine important in immunologic and inflammatory reactions. Several anti-inflammatory components of perilla leaf have been identified, including luteolin and tormentic acid. 3 , 16 In vitro and in vivo immunoenhancing effects have been described for a crude polysaccharide extract isolated from the leaves of perilla. 17 , 18

Animal data

Topically applied triterpene acids isolated from dried perilla leaves produced a marked reduction in induced ear inflammation in mice. 19 Greatest improvement was observed with the application of tormentic acid, an ursane triterpene. Inhibition of inflammation with this agent was similar to that produced by hydrocortisone and indomethacin. In another study, orally administered perilla leaf extract inhibited acute inflammation in 3 different models, including one for contact dermatitis. 15

Clinical data

Improvement in the symptoms of seasonal allergic rhinoconjuctivitis was reported in a small study (N = 30) of perilla extract enriched with rosmarinic acid. Although objective symptom scores were not affected, patient evaluation of symptoms showed improvement scores of 30%, 55.6%, and 70% for patients receiving placebo, rosmarinic acid 50 mg, and rosmarinic acid 200 mg, respectively ( P = 0.05; placebo vs rosmarinic acid 200 mg). Numbers of inflammatory cells in nasal lavage fluid were significantly lower at 3 days in patients receiving rosmarinic acid. However, this effect was no longer apparent at 21 days. 19 , 20

Cancer
Animal data

The inhibitory effects of topically applied tormentic acid on carcinogenesis have been investigated in mice. 16 Similar results have been observed with topical application of a perilla leaf extract; the active principle in this study was thought to be luteolin. 21 The effects of orally administered perilla leaf extract were less marked, and no difference in numbers of tumors was observed between controls and perilla-treated groups at 20 weeks. Reduction in the incidence of mammary and colonic tumors has been associated with perilla oil dietary supplementation in laboratory animals. 22 , 23 In vitro experiments with human leukemia and hematoma cell lines have demonstrated apoptotic and cell cycle-arresting properties for perilla leaf extract of greater effect than with rosmarinic acid alone. 24 , 25

Clinical data

The constituent perilla alcohol has been studied in skin, prostate, and breast cancers, as well as for glioblastoma. 26 , 27 , 28 , 29

CNS effects
Animal data

In a model of age-related deficits in learning and memory, mice fed a diet enriched with perilla oil exhibited better learning performance and less hyperactive behavior than those fed an alpha-linolenate–deficient diet. 30 Apigenin extracted from perilla was found to have limited antidepressant-like effects in mice. 31 In mice with stress-induced depression, perillaldehyde reduced the duration of immobility in the forced swimming test. 32 An anorexigenic effect has been demonstrated in mice fed apigenin both acutely and after 30 days, with no effect on blood glucose or total cholesterol but with decreased triglycerides. 33 In vitro studies suggest chemical constituents of perilla may act via the monoamine transport system to increase monoamine levels and via inhibition of beta-sectretase enzymes to reduce the production of amyloid protein. 34 , 35

Clinical data

Research reveals no clinical data regarding the use of perilla in diseases of the central nervous system.

Other uses
Antimicrobial

Luteolin, extracted from perilla seed oil, showed marked antimicrobial activity against bacteria commonly associated with dental caries. 36 Activity of perilla oil against toxins produced by Staphylococcus aureus has been demonstrated. 37

Dermatology

Perilla leaf extract has been shown to inhibit tyrosinase and melatonin synthesis in mice melanoma cells, suggesting potential applications for skin lightening. 38

Dietary

Perilla oil is rich in alpha-linolenate; health benefits have been theorized with its use. Serum cholesterol and triglyceride levels decreased in rats fed perilla oil. Beneficial changes in the levels of eicosapentaenoic acid and arachidonic acid were also observed in these animals. 39 A trend toward decreased lipid peroxidation was observed in a small study among healthy volunteers who consumed 5 g of powdered perilla leaves for 10 days. 11

Glomerulonephritis

An orally administered perilla leaf decoction resulted in reductions in proteinuria and in the numbers of glomerular and proliferative cell nuclear antigen-positive cells in animals with mesangioproliferative glomerulonephritis. 40

Dosage

Clinical trials are lacking to provide dosage recommendations. An extract of perilla enriched to contain 200 mg of rosmarinic acid has been used to treat the symptoms of seasonal allergy. 19 Healthy volunteers consumed 5 g of powdered perilla leaves for 10 days in another study. 11

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Dermatitis has been reported in perilla oil workers. Patch testing suggests that 1-perillaldehyde and perilla alcohol contained in the oil are responsible for the effect. 2 , 41 Two cases of anaphylaxis resulting from oral consumption of 500 mg of perilla seeds have been reported. An IgE-mediated response was documented. 42

Toxicology

Animals grazing on perilla have developed fatal pulmonary edema and respiratory distress. 43 Perilla ketone, chemically related to the toxic ipomeanols derived from moldy sweet potatoes, is a potent agent for the induction of pulmonary edema in laboratory animals. 44 Highest levels of perilla ketone occur in the plant during the flowering and seed stages. 1 It acts by increasing the permeability of endothelial cells and may not require the presence of cytochrome P450 to increase vascular permeability. 45

The toxicity of perilla ketone has been examined in several animal species. 43 Low intraperitoneal median lethal dose values were observed for mice and hamsters (5 and 13.7 mg/kg, respectively), with far higher lethal doses being required for dogs and pigs (106 and 158 mg/kg, respectively). Perilla ketone-related pathology in dogs and pigs was primarily hepatic, with only minor pulmonary effects, while mice and hamsters displayed only pulmonary lesions. Enzyme bioactivation of perilla ketone may be required for toxicosis, with species unable to produce the perilla metabolite having reduced susceptibility to its poisoning. The volatile perilla oil contains the aldehyde antioxide that has been used in the tobacco industry as a sweetener; however, this compound may be toxic.

Bibliography

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17. Kwon KH, Kim KI, Jun WJ, Shin DH, Cho HY, Hong BS. In vitro and in vivo effects of macrophage-stimulatory polysaccharide from the leaves of Perilla frutescens var. crispa. Biol Pharm Bull . 2002;25(3):367-371.
18. Jin CH, Lee HJ, Park YD, et al. Isoegomaketone inhibits lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages through the heme oxygenase-1 induction and inhibition of the interferon-beta-STAT-1 pathway. J Agric Food Chem . 2010;58(2):860-867.
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20. Guo R, Pittler MH, Ernst E. Herbal medicines for the treatment of allergic rhinitis: a systematic review. Ann Allergy Asthma Immunol . 2007;99(6):483-495.
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24. Kwak CS, Yeo EJ, Moon SC, et al. Perilla leaf, Perilla frutescens , induces apoptosis and G1 phase arrest in human leukemia HL-60 cells through the combinations of death receptor-mediated, mitochondrial, and endoplasmic reticulum stress-induced pathways. J Med Food . 2009;12(3):508-517.
25. Lin CS, Kuo CL, Wang JP, Cheng JS, Huang ZW, Chen CF. Growth inhibitory and apoptosis inducing effect of Perilla frutescens extract on human hepatoma HepG2 cells. J Ethnopharmacol . 2007;112(3):557-567.
26. Stratton SP, Alberts DS, Einspahr JG, et al. A phase 2a study of topical perillyl alcohol cream for the chemoprevention of skin cancer. Cancer Prev Res (Phila) . 2010;3(2):160-169.
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28. Liu G, Oettel K, Bailey H, et al. Phase II trial of perillyl alcohol (NSC 641066) administered daily in patients with metastatic androgen independent prostate cancer. Invest New Drugs . 2003;21(3):367-372.
29. da Fonseca CO, Schwartsmann G, Fischer J, et al. Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surg Neurol . 2008;70(3):259-266; discussion 266-267.
30. Umezawa M, Kogishi K, Yoshimura S, et al. High-linoleate and high-alpha-linolenate diets affect learning ability and natural behavior in SAMR1 mice. J Nutr . 1999;129(2):431-437.
31. Nakazawa T, Yasuda T, Ueda J, Ohsawa K. Antidepressant-like effects of apigenin and 2,4,5-trimethoxycinnamic acid from Perilla frutescens in the forced swimming test. Biol Pharm Bull . 2003;26(4):474-480.
32. Ito N, Nagai T, Oikawa T, Yamada H, Hanawa T. Antidepressant-like effect of l-perillaldehyde in stress-induced depression-like model mice through regulation of the olfactory nervous system. Evid Based Complement Alternat Med . 2008 Jul 16. [Epub ahead of print]
33. Myoung HJ, Kim G, Nam KW. Apigenin isolated from the seeds of Perilla frutescens britton var crispa (Benth.) inhibits food intake in C57BL/6J mice. Arch Pharm Res . 2010;33(11):1741-1746.
34. Zhao G, Qin GW, Wang J, Chu WJ, Guo LH. Functional activation of monoamine transporters by luteolin and apigenin isolated from the fruit of Perilla frutescens (L.) Britt. Neurochem Int . 2010;56(1):168-176.
35. Choi SH, Hur JM, Yang EJ, et al. Beta-secretase (BACE1) inhibitors from Perilla frutescens var. acuta. Arch Pharm Res . 2008;31(2):183-187.
36. Yamamoto H, Ogawa T. Antimicrobial activity of perilla seed polyphenols against oral pathogenic bacteria. Biosci Biotechnol Biochem . 2002;66(4):921-924.
37. Qiu J, Zhang X, Luo M, et al. Subinhibitory concentrations of perilla oil affect the expression of secreted virulence factor genes in Staphylococcus aureus . PLoS One . 2011;6(1):e16160.
38. Hwang JH, Lee BM. Inhibitory effects of plant extracts on tyrosinase, L-DOPA oxidation, and melanin synthesis. J Toxicol Environ Health A . 2007;70(5):393-407.
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40. Makino T, Nakamura T, Ono T, Muso E, Honda G. Suppressive effects of Perilla frutescens on mesangioproliferative glomerulonephritis in rats. Biol Pharm Bull . 2001;24(2):172-175.
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42. Jeong YY, Park HS, Choi JH, Kim SH, Min KU. Two cases of anaphylaxis caused by perilla seed. J Allergy Clin Immunol . 2006;117(6):1505-1506.
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44. Abernathy VJ, Roselli RJ, Parker RE, Pou NA. Effects of Perilla ketone on the in situ sheep lung. J Appl Physiol . 1992;72(2):505-514.
45. Waters CM, Alexander JS, Harris TR, Haselton FR. Perilla ketone increases endothilial cell monolayer permeability in vitro. J Appl Physiol . 1993;74(5):2493-2501.

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