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. 2023 Mar 15;15(3):369–375. doi: 10.1016/j.chmed.2023.03.002

Perilla frutescens: A traditional medicine and food homologous plant

Xinling Wu a,b,c, Shuting Dong b,c, Hongyu Chen b,c, Miaoxian Guo b,c, Zhiying Sun a,⁎, Hongmei Luo b,c,⁎
PMCID: PMC10394348  PMID: 37538863

Abstract

Perilla frutescens, an annual herb of the Labiatae family, has been cultivated in China for more than 2000 years. P. frutescens is the one of the first medicinal and edible plant published by the Ministry of Health. Its leaves, stems and seeds can be used as medicine and edible food. Because of the abundant nutrients and bioactive components in this plant, P. frutescens has been studied extensively in medicine, food, health care and chemical fields with great prospects for development. This paper reviews the cultivation history, chemical compositions and pharmacological activities of P. frutescens, which provides a reference for the development and utilization of P. frutescens resources.

Keywords: bioactive compounds, medicine and food homology, Perilla frutescens (L.) Britt, pharmacological activities

1. Introduction

Perilla frutescens (L.) Britt. is an annual herb with medicine and food homology of the Labiatae family and its dried stems, leaves and seeds have been used as medicinal materials in traditional Chinese medicine (TCM). The earliest historical record of P. frutescens can be traced back to the Western Han Dynasty (202BCE − 220 CE) and has been cultivated for more than two thousand years in China. According to the Compendium of Materia Medica, the leaves of P. frutescens could be eaten with vegetables, brined with sour plums or salt as a side dish, or boiled into soup for drinking. In daily diet, the leaves of P. frutescens are used in barbecue, sashimi, sushi; with ginger or lotus leaves in tea; also used as a seasoning for cooking meat to add flavor. However, the ingestion of both P. frutescens leaves and crucian carp in daily diet should be avoided because it may cause toxic sores. The seed oil of P. frutescens can be added to food, and eaten directly after stirring. The seed oil of P. frutescens is also used as a substitute for hydrogenated oil or cream in baking pastries. The medicinal use of P. frutescens was first recorded in Miscellaneous Records of Famous Physicians (Mingyi Bielu in Chinese), which is a collection of successive generations of materia medica, covered a total of 730 kinds of drugs in this ancient book.

The Compendium of Materia Medical is the most complete and extensive medical book in the history of Chinese medicine. The plants of P. frutescens were grouped into two species in the ancient book: those with green leaves on the upper and lower surfaces classified to Baisu, and those with red or purple on the lower of the leaves classified to Zisu (Fig. 1). The modern taxonomist E. D. Merrill attributed the differences of leaf color to the cultivation and classified them as varieties. According to morphological differences, the species of domestic P. frutescens mainly includes Perilla frutescens (L.) Britt. var. frutescens, P. frutescens var. purpurascens (Hayata) H. W. Li. P. frutescens var. auriculatodentata C. Y. Wu & Hsuan ex H. W. Li, P. frutescens var. auriculato-dentata C. Y. Wu & S. J. Hsuan ex H. W. Li. and P. frutescens var. crispa (Thunb.) Hand.-Mazz. Based on the main chemical composition of the volatile oil in P. frutescens, the plants of P. frutescens are categorized into monoterpene (MT) and phenylpropylene (PP) type. The MT-type P. frutescens are further composed of seven sub-types, including perillaldehyde (PA), perilla ketone (PK), citral (C, a mixture of neral and geranial), perillen (PL), PT (piperitenone), SF (shisofuran), and elsholtziaketone (EK). PP-m type mainly consists of myristin, PP-dm type mainly consists of dillapiol and myristin, PP-em type mainly consists of elemicin and myristin, PP-dem type mainly includes dilapidil, elemicin and myristin, and PP-dmn type mainly consists of dillapiol, myristin and nothoapiol. (Ito et al., 1999). The edible P. frutescens has been used as spice all over the world because of its unique flavor. The chemical constituents and biological activities of P. frutescens have been extensively studied (Hou et al., 2022).

Fig. 1.

Fig. 1

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Leaf morphology of P. frutescens. (A) The leaves of Zisu usually have red or purple on the lower surface with a strong fragrance. (B) The leaves of Baisu are often green with a faint fragrance.

2. Why does P. frutescens have homology of medicine and food?

2.1. Application of P. frutescens

2.1.1. Application of P. frutescens in TCM formulae

The medicinal use of P. frutescens has been widely recorded in TCM formulae. According to the Thousand Gold Formula (Qian Jin Fang), one of the classical books of ancient Chinese medicine, the juice of the P. frutescens leaves was used to treat the bites of poisonous snakes. P. frutescens has been used to relieve abdominal pain caused by overconsumption of fish and crab in Synopsis of Prescriptions of the Golden Chamber (Jin Gui Yao Lüe). In Prescriptions for Universal Relief (Pu Ji Fang), P. frutescens was also widely used for the sores. The combination of the P. frutescens leaves with mulberry leaves had effect on stopping bleeding from wounds caused by metal instruments in Yong Lei Qian Fang.

P. frutescens had the function of treating cough in several formulas, such as Perilla Fruit Powder (Su Zi San) in Materia Medica of Southern Yunnan (Dian Nan Ben Cao), Perilla Decoction (Zi Su Yin) in Bo Ji Fang and Perilla Powder (Zi Su San) in Experiential Prescriptions for Universal Relief (Pu Ji Ben Shi Fang). Perilla Fruit Decoction (Zi Su Zi Tang) in Essential Recipes Worth a Thousand Gold for Emergent (Bei Ji Qian Jin Yao Fang) had curative effect of athlete's foot. In Taiping Holy Prescriptions for Universal Relief (Tai Ping Sheng Hui Fang), Perilla Decoction (Zi Su Tang) was used for the treatment of anasarca due to diabetes.

2.1.2. Application of P. frutescens in food

The boiled leaves of P. frutescens, cold and dressed with sauce had a nourishing effect on the skin. Cooked rice with P. frutescens leaves juice and brown sugar had the ability to prevent influenza. The washed P. frutescens leaves can be wrapped with flour and fried until both sides turn golden before serving. P. frutescens leaves can also be used to make tea and scrambled eggs. In addition, P. frutescens can be used as an ingredient to cook with meat, which was beneficial to remove the fishy aroma and make the meat carry the special aroma of P. frutescens.

2.2. Biological activities of P. frutescens

According to modern biological and pharmacological research on P. frutescens, this medicinal plant exhibits a variety of biological activities, including anti-inflammatory, antibacterial and antifungal, antidepressant, anticancer, anti-obesity, antioxidant, anti-osteoporosis, anti-ulcer and other activities.

2.2.1. Anti-inflammatory activity

The anti-inflammatory activity of PK-type monoterpenoids, alkaloids, and glycoglycerolipids, via inhibiting the inflammatory mediator and pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6) in lipopolysaccharide-stimulated RAW264.7 cells, which contributed to the significant anti-inflammatory effect of P. frutescens (Wang et al., 2018, Zi et al., 2021). The extracts of P. frutescens leaves were useful in the treatment of respiratory disorders such as chronic obstructive pulmonary disease and allergic airway inflammation (Yuan et al., 2022, Yang et al., 2020). The addition of the essential oil isolated from P. frutescens to the diet played the role in controlling pro-inflammatory gene expression and attenuating colitis in mice (Thomas, Cha, & Kim, 2020). The radiation-induced mutant of P. frutescens was determined to alleviate arthritis effectively, and its therapeutic effect was more significant than that of the wild-type plants (Jin, So, Kim, Han, & Kim, 2019).

2.2.2. Antibacterial and antifungal activities

PA is a natural antimicrobial agent, which has been proved to be loaded onto gelatin/zein polymer to prolong the shelf life of frozen chicken (Wang et al., 2021). For mice with oropharyngeal candidiasis, PA was verified to reduce the level of Candida albicans and oral inflammation and inhibit the apoptosis of normal cells to improve the survival rate of mice (Chen et al., 2020). P. frutescens essential oil inhibited bacterial reproduction and prevented food deterioration through damaging the cell membrane of Enterococcus faecalis (Zhou et al., 2020).

2.2.3. Antidepressant activity

Depression is a common global disease, affecting about 3.8% of the world's population. Long-term administration of PA reduced the level of inflammatory mediators in the rat model of chronic unpredictable mild stress (CUMS) by regulating the expression of TXNIP/TRX/NLRP3 in hippocampus CA4, thus alleviating the CUMS-induced depressive behavior (Song et al., 2018). Luteolin-7-O-glucuronide was used to meliorate the depression-like and stress-coping behaviors induced by sleep deprivation (Ryu et al., 2022). Based on the promotion on the expression of brain-derived neurotrophic factors in the rats, the seed oil of P. frutescens was tested to have anti-depressant activities (Lee, Ko, Huang, Chu, & Huang, 2014).

2.2.4. Anticancer activity

The anthocyanins of P. frutescens induced the apoptosis of Hela cells in a dose dependent manner (He, Yao, & Chang, 2015). The extracts of P. frutescens leaves effectively inhibited the cell growth, colony formation, adhesion and metastasis of human colon and lung cancer, which indicated the anti-cancer activity of these ingredients in vitro (Kwak & Ju, 2015). PA has been proved to suppress the proliferation, invasion and migration of prostate cancer cells PC-3 and inhibit the osteoclast differentiation and bone metastasis in RAW264.7 cells (Lin et al., 2022). PA can also increase the level of autophagy-related proteins and inhibit the growth of gastric cancer in a previous study (Zhang et al., 2019).

2.2.5. Other activities

The compounds extracted from P. frutescens by n-butanol had anti-androgen effect and promoted the hair growth of mice (Li et al., 2018). The anti-obesity properties of P. frutescens enable this plant to be further developed as a harmless weight-loss drug (Thomas, Kim, Lee, & Cha, 2018). Rosmarinic acid rich fraction of the seed meal of P. frutescens (PSM) has the effect on weakening osteoclast differentiation and preventing osteoporosis (Phromnoi et al., 2021). The intake of the seed oil of P. frutescens was beneficial to reduce the cognitive and mental decline caused by aging, which may be related to the antioxidant capacity of the alpha-linolenic acid (ALA) in the seed oil of P. frutescens (Hashimoto et al., 2021). The unsaponifiable matter in PSM could resist the skin damage induced by ultraviolet B (UVB), which resulted from the inhibition on the production of UVB-induced reactive oxygen species in Hs68 cells by PSM and the promotion of collagen synthesis (Lee, Sung, Kim, Jeong, & Lee, 2019). Moreover, the application of P. frutescens for industrialization also deserves to follow with interest. Adding the extract of P. frutescens leaves to surimi balls could improve the taste of the surimi balls (Zhao et al., 2019). As a food additive, the seed meal of P. frutescens was able to effectively improve the fatty acid composition of pan-fried chicken patties through significantly reducing its protein oxidation and the content of heterocyclic amines (Khan et al., 2022). The addition of P. frutescens seeds to the dietary led to change the water content, crude protein, free amino acids and ω-3 fatty acid composition of black pork, which was beneficial to improve the quality and nutritional value of black pork (Xia et al., 2022). The extract of the P. frutescens seeds possessed the activity to improve the barrier function of the intestinal mucosa and increase the digestibility of nutrients, which played a positive role in the growth of weaned piglets (Li et al., 2022).

In particular, PK has a certain degree of pulmonary toxicity (Coggeshall et al., 1987). Although only a few people have allergic reactions to the seeds of P. frutescens, it is recommended to limit the intake of PK-type P. frutescens when eating food containing the P. frutescens seeds (Jeong, Park, Choi, Kim, & Min, 2006).

2.3. Chemical components of P. frutescens

The plants of P. frutescens contains diverse of chemical components, mainly including volatile oils, flavonoids, phenolic acids, anthocyanins, polysaccharides, triterpenes, and steroids (Yu et al., 2017). Notably, the isolation, identification and biosynthesis of terpenes, flavonoids, and ALA have been focused and made significant progress in P. frutescens.

2.3.1. Terpenes and biosynthesis

The major terpenes of the volatile oils of P. frutescens are monoterpenes and sesquiterpenes. Among the components isolated from P. frutescens, PA, PK, geraniol, linalool, limonene, and menthone belong to monoterpenes; while farnesene, nerolidol, germacrane, and elemene are sesquiterpenes (Hou et al., 2022). In the PK-type P. frutescens, PK, egomaketone and isoegomaketone are the most abundant compounds (Seo & Baek, 2009). As the major ingredients of the aromatic scent of P. frutescens, PA and PK produced the unique flavor by activating the transient receptor potential A1 (TRPA1) channel (Bassoli et al., 2009).

The terpenes were biosynthesized from geranyl diphosphate (GDP) under the catalysis of terpene synthase (TPS) and several modifier enzymes. In detail, GDP was catalyzed by limonene synthase to produce limonene (Ito et al., 2000, Yuba et al., 1996), and then cytochrome P450 catalyzed the hydroxylation of limonene at the C7 position to synthesize perillyl alcohol (Fujiwara and Ito, 2017, Mau et al., 2010), which was then oxidized to produce PA (Fujiwara and Ito, 2017, Sato-Masumoto and Ito, 2014a). The enzymes of isopiperitenol dehydrogenases 1 and 2 (ISPD1 and ISPD2) catalyzed the conversion of isopiperitenol to isopiperitenone, but only ISPD2 was isolated from the PT-type P. frutescens (Sato-Masumoto & Ito, 2014b). Geraniol synthase catalyzed the production of geraniol (Ito and Honda, 2007, Masumoto et al., 2010), while aldo–keto reductase (AKR) and geraniol dehydrogenase (GeDH) catalyzed the production of citral from geraniol (Sato-Masumoto & Ito, 2014a). The hydroxyl group was introduced into myristicin ether via CYP71D558 to form dillapiole intermediate (Baba, Yamada, & Ito, 2020). The nothoapiole intermediate was synthesized by using apiole and dillapiole as substrates under the catalysis of CYP71D174 (Baba & Ito, 2021). The genes involved in the biosynthetic pathways of terpenes in P. frutescens were summarized in Table 1 and the biosynthetic pathways were shown in Fig. 2.

Table 1.

Identified genes involved in biosynthetic pathways of terpenes in P. frutescens.

GenBank Accession No. Function References
AF233894
D49368 		Limonene synthase Ito et al., 2000, Yuba et al., 1996
DQ088667
DQ234299
DQ234298
DQ234300
FJ644547
FJ644545 		Geraniol synthase Ito and Honda, 2007, Masumoto et al., 2010
GQ120438 Limonene-7-hydroxylase Mau, Karp, Ito, Honda, & Croteau, 2010
KU674339 Catalyzed hydroxylation of limonene to produce perillyl alcohol and catalyzed dehydrogenation of perillyl alcohol to produce perillaldehyde Fujiwara & Ito, 2017
JX629451
JX855836
JX629452
JX855837
jX629453
JX855838 		Catalyzed geraniol to neral and geranial, catalyzed perillyl alcohol to perillyl aldehyde Sato-Masumoto & Ito, 2014a
KF766526
KF766527
KF766528
KF766529 		Catalyzed isopiperitenol to isopiperitenone Sato-Masumoto & Ito, 2014b
LC596386 Bioynthesis of intermediates of nothoapiole catalyzed by apiole and diapiole as substrates Baba & Ito, 2021
LC476554 Taking the myristicin as a substrate to
form dillapiole intermediate		 Baba, Yamada, & Ito, 2020
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Fig. 2.

Fig. 2

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Putative biosynthetic pathways of terpenes in P. frutescens. 1, limonene synthase; 2. limonene-7-hydroxylase; 3. CYP71AT146; 4. ISPD2; 5. geraniol synthase; 6, AKR/GeDH; 7. CYP71D558; 8. CYP71D174.

2.3.2. Flavonoids and biosynthesis

A variety number of flavonoids have been isolated from P. frutescens, including luteolin, apigenin, luteolin-7-O-glucuronide, catechin, vicenin-2, etc (Yu et al., 2017). In Japan, P. frutescens is often used to color beverages because it is rich in anthocyanins (Fujiwara et al., 2018). Flavonoids have multiple biological activities, such as anti-cancer, antiparasis, anti-aging, and antiviral properties (Dias, Pinto, & Silva, 2021).

The anthocyanin content of P. frutescens determines the color of the leaves and stems for this plant. The P. frutescens with red leaves and stems contains large amounts of anthocyanins, whereas the P. frutescens with green leaves and stems contains only trace of anthocyanins, which are accumulated in a single layer of epidermal cells in the leaves and stems (Yamazaki et al., 2003). The leaves of P. frutescens were sensitive to light intensity, which had a significant effect on the expression of genes related to the biosynthesis of flavonoids and anthocyanin in leaves of P. frutescens (Xie et al., 2022). Most of the genes related to anthocyanin biosynthesis have been isolated and identified in P. frutescens (Gong et al., 1997, Saito et al., 1999, Yamazaki et al., 1999, Yamazaki and Saito, 2006, Yamazaki et al., 2008, Kitada et al., 2001, Yonekura-Sakakibara et al., 2000) (Fig. 3). The genes encoding anthocyanin biosynthetic enzymes were only specifically expressed and accumulated in P. frutescens with red or purple leaves and stems, which was consistent with the pattern of the anthocyanin accumulation (Gong et al., 1997, Yamazaki et al., 2008, Kitada et al., 2001).

Fig. 3.

Fig. 3

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Flavonoid biosynthetic pathway in P. frutescens. The purple background represents the anthocyanin biosynthetic pathway. The genes in red mean the genes have been identified in P. frutescens. PAL, phenylalanine ammonia lyase; C4H, cinnamate 4-hydroxylase; 4CL, 4-coumarate-CoA ligase; CHS, chalcone synthase; CHI, chalcone isomerase; FSII, flavone synthase II; F3H, flavanone 3-hydroxylase; F3′H, flavonoid 3′-hydroxylase; DFR, dihydroflavonol reductase; ANS, anthocyanin synthase; 3-GT, flavonoid 3-O-glucosyltransferase; AAT, anthocyanin acyltransferase; 5-GT, anthocyanin 5-O-glucosyltransferase; MAT, Malonyl-CoA: anthocyanin malonyltransferase.

2.3.3. ALA and biosynthesis

The seeds of P. frutescens contains large amount of fatty acids, such as ALA, stearic acid, oleic acid, palmitic acid, arachidonic acid, myristic acid, etc (Yu et al., 2017). ALA is an essential fatty acid which possesses anti-inflammatory, anti-allergic, anti-tumor, anti-cancer and cardiovascular protective bioactivities (Fan et al., 2022, Kim et al., 2020, Rodriguez-Leyva et al., 2010, Wang et al., 2022, Yang et al., 2013).

The content of ALA in the seed oil of P. frutescens is more than 60%, which is related to the biosynthesis and metabolism of fatty acids in P. frutescens. A number of genes involved in the fatty acid biosynthetic pathway have been isolated and identified in P. frutescens, such as fatty acid desaturase (FAD) (Chung et al., 1999, Lee et al., 2016) and 3-ketoacyl-ACP synthase (KAS) (Hwang, Kim, & Hwang, 2000). According to the transcriptome data analysis, the accumulation of saturated fatty acids in the seeds of P. frutescens is mainly during 5–15 d after flowering (Liao et al., 2018), and six transcription factor (TF) families (MYB, AP2/ERF, bHLH, MADS-box, Zinc finger and NAC) were involved in regulating the expression of desaturase gene in P. frutescens (Zhang et al., 2017).

3. Reflections on development of P. frutescens

At present, there are a large number of P. frutescens varieties with similar phenotypes widely cultivated and grown in China, which leads to the difficulty of sample accurate identification and further brings the potential risks for drug safety. Cultivation conditions also affect the content of bioactive components in P. frutescens, which plays an important role in affecting the medicinal and edible quality of this plant (Pan et al., 2018, Shen et al., 2018). Therefore, the cultivation of P. frutescens varieties with high-yield and safe for medicinal and edible uses, and optimization of planting conditions and patterns are important issues facing to the current research of P. frutescens.

Although P. frutescens is not usually infected by viruses due to its strong flavor, the mosaic disease is a common bacterial infection of P. frutescens in recent years, which seriously affected the production of P. frutescens (Kubota et al., 2020). Using pesticides in the cultivation process can reduce the impact of diseases on P. frutescens. However, the use of pesticides may cause pesticide residues in P. frutescens, and even affect the quality and safety of P. frutescens, and endanger human health. Although several studies have shown that the pesticide residues in P. frutescens are not harmful to humans (Noh et al., 2019, Sardar et al., 2022), it is still necessary to seek safer and more environment-friendly technologies to control the diseases of P. frutescens.

The whole plant of P. frutescens contains diverse compounds with important bioactivities. So far, about 400 compounds have been isolated and identified in P. frutescens. However, some compounds are difficult to be separated and purified due to their complex structures or low content, which hinders the research on the pharmacological and biological activities of these bioactive compounds. Therefore, it is necessary and promising to optimize the extraction process of these compounds and carry out the synthetic biology research of the important bioactive components of P. frutescens. Most studies on the pharmacological activities of P. frutescens mainly focus on the bioactive components of the P. frutescens leaves, while the pharmacological studies on the compounds isolated from the P. frutescens seeds are very limited. Furthermore, the toxicity and pharmacokinetics the bioactive compounds of P. frutescens are very insufficient, and the application of these components in the clinical research of human diseases is still rare. Therefore, it is urgent to accelerate the transformation of research results of P. frutescens from laboratory to clinical application.

A lot of TCM preparations, cosmetics, dietary supplements and other products have been developed based on the pharmacological properties of the P. frutescens leaves. The seeds of P. frutescens are rich in ALA, which is an unsaturated fatty acid that is essential to human body but cannot be synthesized by itself. The developed dietary supplements such as the capsules of P. frutescens seed oil and the biscuits of P. frutescens seeds help to supplement ALA in the body.

4. Conclusion

P. frutescens, one of the first medicinal and edible plant published by the Ministry of Health, has been widely studied and applied in medicine, oil, fragrance, spices and food with high application value and industrial prospects. The plants of P. frutescens are rich in terpenes, flavonoids and ALA, which are the main bioactive components with antibacterial, anti-inflammatory, anti-tumor and antioxidant activities. Moreover, the crude proteins, crude fibers, carotenoids, vitamins, and carbohydrates are also abundant in P. frutescens. These abundant chemical compositions of P. frutescens are the material basis of its homology as medicine and food. Clarification of biosynthesis and regulation mechanism of these important compounds can facilitate to improve the accumulation of bioactive components through genetic engineering or gene editing technology, which will help to enrich the germplasm resources and improve the quality of P. frutescens. However, the P. frutescens-related industry also faces many challenges. The normalized cultivation, improvement of the yield and quality and promotion of transformation of research results are the urgent problems to be solved to ensure the safety of the medicinal and edible products of P. frutescens. The solution of these problems will lay a foundation for promoting the development and economic growth of the P. frutescens industry in our country.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81973422) and the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-071).

Contributor Information

Zhiying Sun, Email: szyww@126.com.

Hongmei Luo, Email: hmluo@implad.ac.cn.

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