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. 2018 Aug 27;7(6):1012–1019. doi: 10.1039/c8tx00141c

Phototoxicity of traditional chinese medicine (TCM)

Xiaoqi Li a, Rui An a, Kun Liang a, Xinhong Wang a, Lisha You a,✉
PMCID: PMC6240804  PMID: 30542599

graphic file with name c8tx00141c-ga.jpgPhototoxicity can cause toxic responses such as edemas and lesions, and is one of the severe adverse effects that largely limit the use of these phototoxic drugs.

Abstract

Phototoxicity can cause toxic responses such as edemas and lesions, and is one of the severe adverse effects that largely limit the use of these phototoxic drugs. Some traditional Chinese medicines (TCMs) and their constituents have been reported to be phototoxic. However, to date, their phototoxicity information is still very limited, and lacks systemic investigation. This article presents the phototoxicity potential of various types of TCMs and their active components in an effort to provide valuable information for drug research and discovery to mitigate phototoxicity concerns. Some potential mechanisms of action (MoAs) of phototoxicity are discussed. In addition, in vivo and in vitro phototoxicity assays are summarized this review.

1. Introduction

TCMs have been used as a common remedy to treat various diseases in China for thousands of years. In recent years, TCMs have become increasingly and widely accepted by the global community as a complementary and alternative medicine. According to the ‘Report on general status of TCM in 2009’ issued by the Chinese State Administration in 2014,1 one fifth of patients in China prefer TCM doctors as their first choice, while a quarter of patients prefer to treat their illnesses through medicines other than TCM. There are many types of TCMs that are incorporated in clinical treatment. However, the safety of some of these TCMs has not been fully investigated and understood according to the modern western drug standards.2–4 With the increase in globalization and popularity of TCMs, safety awareness and regulation need to be paid considerable attention and strengthened as compared with western drugs.5–7

Phototoxicity refers to the presence of inflammation in the skin when exposed to ultraviolet radiation or sunlight during the administration of a phototoxic drug.8–10 The degree of phototoxicity is positively correlated with the time of irradiation and the amount of the phototoxic drug. The longer the exposure time in the sunlight and the higher the amount of phototoxic drugs taken and more severe would be the phototoxic reaction. A phototoxic reaction is a double-edged sword. On the one hand, patients will suffer from fever, edema, herpes and other symptoms. On the other hand, patients may also suffer from severe diseases such as skin cancer. Moreover, phototoxicity can cause eye damage, resulting in ocular cataracts.10,11 If there is a phototoxic reaction, preventive measures should be taken in a timely manner and the patient should avoid exposure to sunlight.

Recently, many different classes of drugs have been reported to be activated by solar radiation and stimulate a phototoxic response in the skin.12 Photoactivated molecules may elicit harmful effects including phototoxicity (e.g., erythema, oedema, and pigmentary alterations), photoallergy, and photocarcinogenity.13 For this reason, evaluation of phototoxic hazards of TCM will be highly critical and necessary for the incorporation of TCMs in the health industry. In this review, we will summarize the phototoxicity of some TCMs and their major phototoxic constituents. In addition, we will examine the general mechanisms of phototoxicity of TCM, including several representative phototoxic plants and their active chemical constituents.

2. TCMs with phototoxicity

2.1. Flavonoids

Flavonoids are a group of polyphenolic compounds, with diverse chemical structures and characteristics, and ubiquitous in TCM plants. There has been an increasing interest in the research of flavonoids due to their versatile health benefits, including anti-inflammatory, antioxidant, antiproliferative, and anticancer activity.14

Recently, a comprehensive study was conducted to examine the phototoxicity of silymarin and its flavonolignans, namely, silybin, isosilybin, silychristin, silydianin and 2,3-dehydrosilybin, by a validated 3T3 NRU assay. The results showed that silymarin, silybin, isosilybin, silychristin and silydianin had no phototoxicity towards any of the cells used. In contrast, 2,3-dehydrosilybin (1) was identified as a compound with phototoxic potential (Fig. 1).15

Fig. 1. The structure of 2,3-dehydrosilybin (1).

Fig. 1

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Hypericum perforatum extracts are mainly used as oral antidepressants. Depending on the source, the extracts may contain various amounts of phenylpropanes, flavonol derivates, biflavones, proathocyanidines, xanthones, phloroglucinoles, some amino acids, naphtodianthrones (hypericines), and essential oil constituents. However, the therapeutic use of hypericum perforatum extracts is limited by their phototoxic potential. Hypericum perforatum extracts have demonstrated cytotoxicity and photocytotoxicity in a dose and UVA-dose dependent manner.16 Hypericin, the main constituent of Hypericum perforatum, also evoked severe phototoxic effects. Thus, it was identified as the main phototoxic constituent with a modified neutral red assay utilizing an immortalized human keratinocyte cell line (HaCaT cells) as substrate and UVA irradiation. Among the tested flavonoids, quercitrin was found to be cytotoxic, while rutin demonstrated phototoxicity. Quercitrin was effective in controlling the phototoxic activity of Hypericum perforatum extracts (Fig. 2).16

Fig. 2. The structure of Rutin (2) and Quercitrin (3).

Fig. 2

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2.2. Coumarins

Furocoumarins are phototoxic and photomutagenic natural plant constituents found in many TCMs.17 Furocoumarins, containing a coumarin structure fused with a furan ring, have been described to exhibit notable phototoxicity. There are two subclasses of furocoumarins: psoralen-type compounds with a linear structure and angelicin-type furocoumarins with an angular structure. The phototoxicity of angular angelicin-type furanocoumarins is much weaker than that of linear psoralen-type furacoumarins.17 This might be because linear furocoumarins (psoralen) can produce both mono- and inter-strand crosslinked di-adducts, while angular type furocoumarins (angelicin) interact with DNA to form only mono-adducts.17

Recently, the photomutagenic potency of linear furocoumarins 5-methoxypsoralen (5-MOP) and 8-methoxypsoralen (8-MOP), angular furocoumarin angelicin, and coumarin limettin was systematically examined.18 Above certain concentrations, all test compounds were more or less phototoxic in the presence of UVA with varying doses between 50 and 200 mJ cm–2. Results highlight that 5-MOP is the most phototoxic compound. These data provided a new concept for the description of the relative photomutagenic potency of coumarins and furocoumarins. In addition, the results indicate that in V79 cells, 8-MOP is less photomutagenic and limettin and angelicin are considerably less photomutagenic than 5-MOP (Fig. 3).

Fig. 3. The names and structures of some furacoumarins and coumarins.

Fig. 3

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2.3. Alkaloid derivatives

Alkaloids are a large class of basic nitrogen compounds widely distributed in nature. Most alkaloids, having a complex heterocyclic structure, are the active ingredients of many traditional Chinese medicinal plants, with a wide range of physiological activities.19 The earliest discovered phototoxic component of alkaloids is berberine, which has been determined to be highly phototoxic.20 Phellodendri Chinensis Cortex (Huang bai) and Coptidis Rhizoma (Huang-lien) are among the most commonly used traditional Chinese medicines in China. By weight, berberine constitutes approximately 0.6%–2.5% and 7%–9% of total content of Huang bai and Huang-lien, respectively.21 Some other alkaloids were detected to be phototoxic including plamatine, canadine, hydrastine, hydrastinine. The name and structure of some alkaloids and dehydrorrolizidine alkaloids are listed in Fig. 4.17

Fig. 4. The names and structures of some alkaloids with phototoxicity.

Fig. 4

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The phototoxicity of a series of pyrrolizidine alkaloids and their metabolites under UVA irradiation have been investigated recently.22 Upon UVA irradiation in the presence of a lipid (e.g., methyl linoleate), all the seven dehydropyrrolizidine alkaloids, namely, (dehydroriddelliine (13), dehydromonocrotaline (14), dehydroretrorsine (15), dehydrosenecionine (16), dehydroseneciphylline (17), dehydrolasiocarpine (18), and dehydroheliotrine (19)), caused lipid peroxidation in a light dose-responsive manner Fig. 5. However, all the pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides did not result in lipid peroxidation. Based on these results, it was proposed that dehydropyrrolizidine alkaloids formed in the liver are translocated in the blood vessels and skin. In addition, exposure to sunlight can lead to secondary photosensitization, skin damage, and skin cancer.22

Fig. 5. Some typical dehydropyrrolizidine alkaloids with phototoxicity.

Fig. 5

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2.4. Curcumin derivatives

Curcumin (20) is a yellow-orange dye derived from the rhizome of the plant Curcuma longa. Curcumin has demonstrated phototoxicity to several species of bacteria under aerobic conditions.23 Recently it was found that curcumin is also phototoxic to mammalian cells on studying a rat basophilic leukemia cell model; this phototoxicity also requires the presence of oxygen.24,25 The phototoxic effect and photochemical properties of curcumin varies with their concentration and the presence of additives.26 For compounds dimethoxycurcumin (21) and bisdemethoxycurcumin (22), the phototoxic effect was further influenced by the addition of PEG 400 during sample preparation. The two naturally occurring curcuminoids, dimethoxycurcumin and bisdemethoxycurcumin, lack one or two of the methoxy groups present on the phenolic rings of curcumin. However, both exhibit strong light absorption at 420–430 nm in organic solvents, denoting the high phototoxicity potential (Fig. 6).26

Fig. 6. Curcumin and its derivatives with phototoxicity.

Fig. 6

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2.5. Anthraquinones

Plants containing aloin A (23), aloe emodin (24), and structurally related anthraquinones have long been used as TCMs. A recent study indicated that incubation of human skin fibroblasts with 20 μM aloe emodin for 18 h followed by irradiation with UV or visible light resulted in significant photocytotoxicity.27 This photocytotoxicity was accompanied by oxidative damage in both cellular DNA and RNA. In contrast, no photocytotoxicity was observed following incubation with up to 500 μM aloin A and irradiation with UVA light. In an attempt to explain the different photobiological properties of aloin A and aloe emodin, laser flash photolysis experiments were performed. The results revealed that the triplet state of aloe emodin was readily formed following photoexcitation. However, no transient intermediates were formed following photoexcitation of aloin A (Fig. 7).

Fig. 7. Structure of aloe A (23) and aloe emodin (24).

Fig. 7

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Hypericum perforatum extracts are used traditionally as herbal medicines for treatment of depression and skin illnesses.28,29 They are now commonly used for treatment of burns, bruises, swelling, anxiety, and depression. However, some of the Hypericum perforatum extracts are phototoxic, mostly due to hypericin.30 Hypericin is a major ingredient of Hypericum perforatum, which has been reported to be phototoxic and photogenotoxic, and the phototoxic effects vary in a dose-dependent and light-dependent manner (Fig. 8).37

Fig. 8. The structure of Hypericin (25).

Fig. 8

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2.6. Other TCMs with phototoxicity

Chamazulene (1,4-dimethyl-7-ethylazulene), a constituent of the Chinese herb Achillea alphina L. (Shi Cao or Yarrow), is used to treat menopause, abdominal pain, and snake bites.31 Chamazulene absorbs UV-visible light, resulting in the formation of degradation products.25,32 Chamazulene was proved to be photomutagenic in Salmonella strain TA102, but not in TA98 or TA100. UVA irradiation of Chamazulene leads to DNA cleavage and photogenotoxicity in Jurkat cells in vitro (Fig. 9).

Fig. 9. The structure of Chamazulene (26).

Fig. 9

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In addition to the abovementioned TCMs, which have been disclosed to be phototoxic, there are increasing reports about other TCMs with phototoxicity concerns, which have been summarized in Table 1.

Table 1. The summary of phototoxic TCMs and their active components.

Species Major components Plant sources Ref.
Coumarin Isoquercitin Angelicae dahuricae radix 33–34
Psoralen Angelicae sinensis radix 33–34
Bergapten (5-MOP) Ruta graveolens, angelicae dahuricae radix 18 and 35
Xanthotoxin (8-MOP) 18 and 35
Peucedanin Ruta graveolens, angelicae dahuricae radix 18 and 35
Byak-angelicine 36
Byak-angelicol 36
Oxypeucedanine Angelicae dahuricae radix 36
Imperatorin Angelicae dahuricae radix 36
Isoimperatorin Angelicae dahuricae radix 36
Phellopterin Angelicae dahuricae radix 36
Anhydrobyakagelicin Ruta graveolens 36
Angelicins Angelicae dahuricae radix 36
Neobyakangelicol Angelicae dahuricae radix 36
Angelicae dahuricae radix, angelicae dahuricae radix 37
Marmesin 37
Angenomalin 37
Anomalin 38
5-Methylangelicin 38
Trimethylpsoralen Angelicae sinensis radix 38
6,7-Dihydroxybergamottin Angelicae sinensis radix 38
Angelol G Angelicae sinensis radix 38
Oxypeucedanin 38
Osthole Angelicae sinensis radix, angelicae sinensis radix 37
Archangelicin 37
Angelicone 37
7-Desmethylsuberosin 37
6,7-Epoxybergamottin 37
4,5-Dihydropsoralen 37
5,7-Dimethoxy coumarin
 
Alkaloid Hypericin St John's wort extract 28–29
Berberine Phellodendri chinensis cortex, coptidis rhizoma 17
Hydrastine 17
Canadine 17
Hydrastinine 17
Dehydroriddelliine Goldenseal 17
Dehydromonocrotaline Pyrrolizidine alkaloids metabolites 17
Dehydroretrorsine Pyrrolizidine alkaloids metabolites 17
Dehydrosenecionine Pyrrolizidine alkaloids metabolites 17
Dehydroseneciphylline Pyrrolizidine alkaloids metabolites 17
Dehydrolasiocarpine Pyrrolizidine alkaloids metabolites 17
Dehydroheliotrine Pyrrolizidine alkaloids metabolites 17
Pyrrolizidine alkaloids metabolites
 
Curcumin derivatives 2,6-Divanillylidenecyclohexanone 25–26
Bisdemethoxycurcumin 25–26
Dimethoxycurcumin 25–26
Methoxycurcumin 25–26
Dehydroxymethoxycurcumin 25–26
 
Lactone Yangonin Kava rhizome extracts 39
7,8-Dihydrokawain Kava rhizome extracts 39
Kawain Kava rhizome extracts 39
7,8-Dihydromethysticin Kava rhizome extracts 39
Methysticin Kava rhizome extracts 39
5,6-Dehydrokawain Kava rhizome extracts 39
 
Volatile oil Azulene Matricaria recutita 40
Guaiazulene Matricaria recutita 40
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3. The possible mechanisms of phototoxicity

A variety of mechanisms involved in phototoxic effects have been thoroughly investigated before.41,42 In general, the generation of adverse phototoxicity response from TCMs may involve one or more pathways as, shown in Fig. 10. There are four major pathways through which excited photosensitizers exert phototoxic effects on biological macromolecules. In the possible pathway of phototoxic skin response, a photoreactive substance may reach the skin via blood flow after systemic administration, resulting in a photochemical reaction that occurs under light exposure and targets the lipid, DNA or proteins. Epidermal cell membranes have a complex lipid composition, which includes fatty acids, phospholipids, ceramide, and cholesterols. Some lipid components tend to exhibit noncovalent associations with the phototoxic compounds.43 Although molecular properties of phototoxic compounds have been investigated using biomimetic micelles, the photochemical behavior of phototoxic compounds in the presence of micelles, liposomes or other biomimetic systems has not been fully elucidated. The most commonly reported process is phototoxicity via oxidative reactions. After absorption of photons at the appropriate wavelength, a chromophore may reach an excited state. The chromophore in its excited state transfers energy or electrons to molecular oxygen and generates ROS such as superoxide anion (O2–). O2– can lead to H2O2 after dismutation. Furthermore, H2O2 can produce the highly toxic hydrogen peroxide (OH–), which can go through the Fenton reaction catalyzed by ferrous ions to generate hydroxyl radical, which is the most powerful free radical that can destroy cellular constituents via reactions with DNA and proteins, generation DNA, and formation of protein-adducts.44

Fig. 10. Potential mechanisms of phototoxicity of TCMs.

Fig. 10

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4. The in vitro and in vivo assays for phototoxicity evaluation

The phototoxicity caused by clinical drugs has aroused people's attention long ago. Traditional phototoxicity tests mainly depend on animal experiments. Animals employed often include Guinea pig, mouse, rat, and BALB/c mice.12,13 The study of phototoxic animals involves a simple experiment and a robust method, but in vivo assays are time-consuming and expensive. The results of in vivo phototoxicity testing in BALB/c mice could coincide with phototoxic potential in humans, but not all drugs exhibit positive skin reactions.45 To reduce the use of animals in accordance with the 3R principles, a validated in vitro method should generally be considered before conducting animal testing.

In the past, the phototoxicity evaluation of some drugs and their light products was performed using some basic in vitro phototoxicity screening tests such as photohemolysis, lipid photoperoxidation, and protein photodamage.46 The phototoxic potential of oriental medicinal plants was examined in vitro using photohemolysis and the Candida albicans test.11 These experimental operations are relatively simple and helpful in the safety evaluation of some drugs, but the accuracy cannot be guaranteed. Some studies need to be performed for further testing. Considerable efforts have been made to develop effective phototoxic assessments as well as analytical and biochemical methodologies for evaluating phototoxic risk. A few of these efforts include in silico prediction models, photochemical screening tools, and in vitro phototoxicity assessments.

The 3T3 NRU-PT is currently the most widely used assay. In many cases, 3T3 NRU-PT could be considered as an initial test for phototoxicity. The high sensitivity of the 3T3 NRU-PT assay results in good negative predictivity. Negative results from the 3T3 NRU-PT assay are generally accepted as sufficient evidence that a substance is not phototoxic. In such case, no further testing is recommended and no direct phototoxicity is anticipated in humans. The 3T3NRU test is an in vitro method for the phototoxicity test of animal skin. It has the characteristics of simple operation, low cost, good reproducibility, short trial period and good correlation with the experimental results in vivo.47

In addition to the above mentioned experiments, in vitro assay systems also include a ROS assay with a UVA simulator, which was developed and validated and provides an alternative method for phototoxicity evaluation. However, negative substances are over-predicted by this assay.48 Derivatives of reactive oxygen metabolites assay include a capillary gel electrophoresis-based photocleavage assay and an IBP assay. Combined use of photochemical/photobiological and PK data have also been proposed as a new screening strategy for predicting in vivo phototoxic risk.49

Human and animal photosafety tests are also described in more recent regulatory guidelines, including the report from the Second ECVAM Workshop on Phototoxicity Testing (Spielmann et al., 2000),50 and the ICH S10 Guidance for Industry, Photosafety Evaluation of Pharmaceuticals (ICH, 2013).51

5. Perspective

With the increase in number of phototoxic events in clinics, phototoxicity is drawing increasing attention as a safety concern in the early stages of drug discovery. As TCMs are widely used by patients, improved pharmacovigilance and pharmacoepidemiology can contribute to valuable safety information that is relevant to clinical use. Hence, more and insightful investigation needs to be conducted, particularly for popularly and widely used TCMs in order to avoid potential severe harm to patients. Some phototoxicity alert-labelling for specific TCMs should also be taken into account to raise public awareness.

The potential mechanisms of the different ingredients in TCMs with phototoxicity may be complex and still not well known. The specific in vitro and/or in vivo models could be utilized to help elucidate these potential phototoxicity mechanisms. More thorough investigation on the phototoxicity of TCMs will also improve the general understanding of phototoxicity and lead to the development of phototoxicity mitigation strategies. Ultimately, these advancements will aid new drug discoveries by improving safety awareness and addressing phototoxicity issues present with TCMs and other drugs.

Abbreviations

MoAs

Mechanisms of action

ROS

Reactive oxygen species

MX

Mexenone

FDA

Food and drug administration

IBP

Intercalator-based photogenotoxicity

3R

Replacement, reduction, refinement

3T3 NRU PT

3T3 neutral red uptake phototoxicity test

OECD

Organization for economic cooperation and development

PK

Pharmacokinetic

UV

Ultraviolet

Conflicts of interest

There are no conflicts of interest to declare.

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