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A systematic review on the safety of Psoraleae Fructus: potential risks, toxic characteristics, underlying mechanisms and detoxification methods

  • Psoraleae Fructus (PF) is an important traditional herbal medicine with a long history of clinical application. It is widely used to treat various diseases, such as osteoporosis, leucoderma and diarrhea. As a traditional nontoxic herb, it has aroused worldwide concern about the potential risks due to increasing adverse reaction events. This article reviews the botany, ancient records of medical uses, adverse reactions, toxicological research advance and detoxification methods of PF. According to clinical studies, liver injury is the most predominant in PF-related adverse reactions. The underlying mechanisms include bile acid metabolism and transport disorders, oxidative stress, mitochondrial damage, inhibition of liver cell regeneration and inflammatory reactions. Furthermore, the potential toxins of PF are summarized. Traditional methods of processing and compatibility will provide reference for reducing the toxicity of PF, which requires further research. In sum, this work systematically summarizes the reserach progress on the safety of PF, which will provide comprehensive insights into the toxicity of PF and facilitate its safe use and future development.
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A systematic review on the safety of Psoraleae Fructus: potential risks, toxic characteristics, underlying mechanisms and detoxification methods

    Corresponding author: E-mails: wangyg@bmi.ac.cn (WANG Yuguang); gaoyue@bmi.ac.cn (GAO Yue)
  • 1. Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China

Abstract: Psoraleae Fructus (PF) is an important traditional herbal medicine with a long history of clinical application. It is widely used to treat various diseases, such as osteoporosis, leucoderma and diarrhea. As a traditional nontoxic herb, it has aroused worldwide concern about the potential risks due to increasing adverse reaction events. This article reviews the botany, ancient records of medical uses, adverse reactions, toxicological research advance and detoxification methods of PF. According to clinical studies, liver injury is the most predominant in PF-related adverse reactions. The underlying mechanisms include bile acid metabolism and transport disorders, oxidative stress, mitochondrial damage, inhibition of liver cell regeneration and inflammatory reactions. Furthermore, the potential toxins of PF are summarized. Traditional methods of processing and compatibility will provide reference for reducing the toxicity of PF, which requires further research. In sum, this work systematically summarizes the reserach progress on the safety of PF, which will provide comprehensive insights into the toxicity of PF and facilitate its safe use and future development.

    • Herbal remedies are increasingly popular around the world in the past decades. Depite the promising efficacy of a large number of herbal products, more frequent adverse events have been seen, which pose great challenges in safe use. As a representative nontoxic medicine, Psoraleae Fructus (PF, the dried fruits of Psoralea corylifolia L.) is widely used in many countries to treat osteoporosis, leucoderma, diarrhea and cardiovascular diseases, and currently not included in the list of toxic herbs in Chinese Pharmacopoeia [1]. However, recent attention has been drawn upon some liver injury reports of PF [2, 3]. A large volume of studies were performed to evaluate the toxicity of PF and its compositions, but less systematic study has been done on their toxicity and potential mechanism of action. This paper was designed to comprehensively summarize the adverse reactions, potential toxicity, molecular mechanisms, and detoxification methods of PF in an effort to facilitate its safe use and promote drug development.

    Botany
    • Psoralea is a large widely distributed genus of herbs throughout tropical and subtropical regions, in which Psoralea corylifolia L. has long been used in traditional Chinese and Ayurvedic medicine. From ancient times to the present, there are countless descriptions about its appearance in herbal books. P. corylifolia L. is an annual upright herb, with a height of 60−150 cm (Fig. 1A). The branches are hard, fully covered with white villi. The leaf blade is broadly ovate with black glandular spots on both sides, and sparsely hairy or nearly glabrous. The pericarp is black and its surface is irregular reticulate. Its dried ripe fruits, Psoraleae Fructus (Bu Gu Zhi in Chinese) are flat and fragrant (Fig. 1B). The whole plant has crucial medicinal properties for the treatment of various diseases, such as leukoderma, menstruation disorder, uterine hemorrhage and lumbago. PF and its pharmaceutical preparations are also widely used to treat bone and skin diseases in China. The main constituents dominate its bioactivities, such as antitumor, anti-inflammatory, anti-oxidant, and osteoblastic effects (Table 1).

      No.BioactivitiesRepresentative compoundsReference
      1 Anticancer Psoralen, isopsoralen and psoralidin [4-7]
      2 Osteoblastic effct Psoralen, bavachin, isobavachin,
      corylin and bakuchiol
      [8-10]
      3 Anti-oxidation Psoralen, isopsoralen, psoralidin, bavachinin, isobavachin, corylifol A, isobavachalcone, and bakuchiol [11, 12]
      4 Anti-inflammation Isopsoralen, psoralidin, bavachin, bavachinin, corylin, corylifol A, bavachalcone, isobavachalcone, and bakuchiol [13-15]
      5 Antimicrobial effect Psoralen, isopsoralen, psoralidin, bavachin, bavachinin, bavachalcone, isobavachalcone, corylifol B, and bakuchiol [16, 17]
      6 Estrogenic effect Psoralen, isopsoralen, psoralidin, bavachin, corylifol A, isobavachalcone, and bakuchiol [18, 19]
      7 Antidepression Psoralen, isopsoralen, and psoralidin [20, 21]
      8 Improving aging-related diseases Bavachin and bavachinin,
      bavachalcone and isobavachalcone
      [22]
      9 Neuroprotection Bavachin and bavachinin,
      bavachalcone and isobavachalcone
      [23]
      10 Improving cardiovascular function Bakuchicin [24]

      Table 1.  The bioactivities and related representative compounds of Psoralea corylifolia L

      Figure 1.  Aerial part (A) and dried ripe fruit (B) of Psoralea corylifolia Linn. (A) is obtained from the Plant Photo Bank of China (http://ppbc.iplant.cn/)

    Ancient Records of PF
    • The earliest record of PF appeared in a Chinese medical book called Lei’s Treatise on Processing of Drugs (Lei Gong Pao Zhi Lun), where its characteristics and medical use were described in detail. It exerted significant effect of reinforcing the kidneys (Bu Shen) to strengthening Yang (Zhuang Yang), relieving chronic diarrhea and enriching the bone marrow. Additionally, PF has fierce property; it should be first soaked in liquor overnight, followed by rinsing with water for three days, before it is steamed for eight hours, and dried under the sun for later use. These descriptions indicated that the potential toxicity of PF had been observed by ancient people, and the processing methods such as alcohol soaking and water rinsing can reduce the toxicity.

      In TCM theories, medicines are potions and poisons with both efficacy and adverse effects. Balancing patient conditions with the potential risks of drugs to be used, Chinese physicians prescribe reasonable dosage with proper compatibility to ensure the efficacy and eliminate harmful effects. Due to the different characteristics of herbs, it is essential to take advantage of their common efficacy and reduce adverse effects. In some medical books, it was mentioned that PF had the property of dryness (Zao). It was clearly represented in Newly Revised Materia Medica (Xin Xiu Ben Cao) that the compatibility of PF and Juglandis Semen prevented the dryness of PF. There were many similar descriptions, for instance PF was rarely used alone, but used in combination with one or two herbs of nourishing Yin. It implied that the current adverse reactions of PF may be related to its dryness.

    Adverse Reactions and Clinical Characteristics
    • In recent years, some PF-related adverse reactions have been reported, such as hepatotoxicity, phototoxic dermatitis and allergy, where liver injury is the most frequent. TIAN et al. systematically analyzed 84 cases of PF adverse reactions raning from 1978 to 2016 [25]. A total of 48 patients were dignosed with liver injury, accounting for 57.14% of all cases. Other clinical studies also indicated the high hepatotoxicity risk of PF. ZHU et al. evaluated 595 inpatients with herb-induced liver injury (HILI) and found that 40 prescriptions contained PF in their medical history [26]. The clinical characteristics of PF-induced hepatotoxicity include patients older than 40 years of age, a higher proportion of women and mixed pattern of liver injury (hepatocellular and cholestatic types) [27-29]. The median number of days from medication to liver injury was about 29 days, and the oral dose was 2.4−4.8 g per day, with the cumulative dose ranging from 3.6−699.6 g. Furthermore, 96.7% of patients recovered after treatment or drug withdrawal. Some factors may increase the risk of liver injury, such as overdosing, taking the raw product, and improper compatibility of PF.

    Advances in Toxicological Studies
    • PF has potential risks in some toxicological studies, inducing liver and kidney injury, reproductive toxicity and photosensitivity toxicity. The hepatotoxicity of PF is a non-negligible challenge with some controversial questions to be solved. Clinical cases of renal or reproductive injury induced by PF are rarely seen, but it is neceeary to closely observe medication response to avoid possible risks. The toxicological research progress of PF is summarized in order to provide a breakthrough in understanding the questions.

    • Over the past decade, liver injury induced by PF has been extensively investigated in rats, mice and zebrafish. Taking an overdose or long-term of PF may lead to obvious hepatotoxicity [30, 31]. Complex mechanisms pose a great challenge to resolve the hepatotoxicity induced by PF. There is still controversy about the type of liver injury induced by PF, for example instinct or idiosyncratic hepatotoxicity. WANG et al. evaluated the effects of the ethanol extract of PF in rats for 28 consecutive days and results demonstrated hepatic cholestasis and instinct liver injury [32]. DUAN et al. utilized quantitative proteomics and metabolomics analysis and found that the alteration of bile acid metabolism was highly associated with liver injury induced by PF [33]. However, some studies suggested that PF and its preparation (Zhuanggu Guanjie Pills) induced T lymphocyte recruitment to the liver on low-dose lipopolysaccharide mediated rats, which may result in idiosyncratic liver injury. ALT and AST significantly increased, several cytokines were over-expressed and an intense inflammatory response was activated in rats. Further metabonomics analysis showed that sphingolipid metabolism and tyrosine metabolism were seriously altered in rats, which partly reflected the mechanism of liver injury [34, 35]. Furthermore, WU et al. found that the compatibility of PF and Paeoniae Radix Rubra attenuated the idiosyncratic hepatotoxicity induced by PF through regulating the arachidonic acid and glycerol phospholipid pathways [36].

      Some efforts have been dedicated to the hepatotoxicity mechanism of PF, which involves bile acid metabolism and transport disorders, oxidative stress, mitochondrial damage, inhibiting liver cell regeneration and repair, and inflammatory reaction (Fig. 2). Bile acid accumulation and hepatocyte apoptosis are the research hub. Coumarins in PF are involved in multiple pathways, and flavonoids induce endoplasmic reticulum stress and interfere with metabolic detoxification. Monoterpene phenols play a role in bile acid transporters. The upstream molecules induced by coumarins include the recombinant farnesoid X receptor (FXR) and protein kinase R-like ER kinase (PERK). However, it remains unclear which factors are the exact triggers of PF-induced liver injury. Systematical and rigorous studies will clearly reveal the onset events and toxic molecules in the process in the near future.

      Figure 2.  Hepatotoxicity mechanisms of PF and its main components

    • Some studies suggested that administration of PF for 21 days led to kidney injury in mice [37]. The histological changes were characterized by enlarged endothelial cells and interstitial nuclei in the capillary plexus and turbidized epithelial cells of the proximal convoluted ducts. Pharmacokinetics research revealed that the CYP450 enzyme was inhibited and the exposure of bakuchiol increased after PF treatment [38]. Besides, psoralen was proven to induce the apoptosis of Hhuman kidney-2 (HK-2) cells [39].

    • WANG et al. found that PF extract reduced the mRNA expression related to steroid hormone production in the adrenal glands and inhibited androgen secretion, leading to damages in the prostate, seminal vesicle and adrenal gland in rats [40]. Diawara et al. found that long-term administration of PF resulted in weak ovarian function, and decreases in ovulation number, estrogen level and uterine quality in female mice [41].

    • The phototoxicity mechanism of PF has been clarified, which is related to the photochemical reaction of a few coumarins, such as psoralen and 8-methoxypsoralen. Contact or oral administration made these photosensitive components distributed in skin tissues, which then significantly increased ultraviolet absorption (250−320 nm), stored energy and produced energy transfer, leading to skin toxicity with erythema epidermis [42, 43].

    Potential Toxic Compounds
    • More than 200 compounds were isolated and identified from PF, including coumarins, flavones, meroterpenes, lipids, and volatile oil [44, 45]. Many constituents and metabolites have significant bioactivities, but some of them demonstrate potential toxicity. These potential toxic compounds have been explored from different perspectives. In the study, they are categorized based on their chemical structures and their toxic characteristics are summarized in Table 2.

      ConstituentsStructural typesOrgansExperimental modelsMechanismsRelated targetsReference
      PsoralenCoumarinThe liverRatsInducing the bile acid transportersCYP7A1, BSEP, MRP2, SULT2A1, FXR and MRP3[46]
      Liver microsome of miceInducing th activity and expression of CYP450 enzymesCYP3A11 and CYP2E1[46]
      HuH-7 and HepaRG cellsInducing the activity of CYP450 enzymesCYP3A4[47]
      HepG2 cellsInducing hepatocyte apoptosis by the endoplasmic reticulum stressGrp78, PERK, eIF2α, ATF4 and ATF6[48]
      The kidneysMale miceAffecting renal organic ion transportersOCT1, OCT2, OCTN1, OCTN2, OAT1, OAT3, URAT1, GLUT9 and MRP4[46]
      The reproductive systemFemale ratsAccelerating estrogen metabolismUGT1A6 and CYP1A1[49, 50]
      Embryonic developmentZebrafishInducing oxidative stress, apoptosis and lipid metabolism pathwaysKeap1, Nrf2, Mn-sod, Cu/Zn-sod, p53, Puma, Bax, Bcl-2, Apaf-1, Caspase-9, Caspase-3, Hmgcra, Pparα and Fas[47]
      IsopsoralenCoumarinThe liverRats
      Inducing the bile acid transports
      CYP7A1, BSEP, MRP2, MRP3, SULT2A1 and FXR; NTCP, MDR1, ABCG5, ABCG8, and OSTα[46, 52]
      Liver microsome of miceInducing the activity and expression of CYP450 enzymesCYP3A11 and CYP2E1[46]
      ZebrafishReducing the antioxidant capacity of the liverLFABP, GSTP2 and SODL[51]
      HepG2 cellsInducing the bile acid transportsMRP2 and MRP3[53]
      The kidneysMale miceAffecting renal organic ion transportersOCT1, OCT2, OCTN1, OCTN2, OAT1, OAT3, URAT1, GLUT9 and MRP4[46]
      PsoralidinCoumarinThe liverFemale miceInducing idiosyncratic liver injury by activating the inflammasomeNLRP3, IL-1β, TNF-α, Caspase-1 and ROS[54]
      BavachinFlavonoidThe liverHuman UGT1A1 enzymeInhibiting bilirubin metabolismUGT1A1[55]
      HepG2 cellsInducing the mitochondrial damage by endoplasmic reticulum stressROS, Mfn2, Akt, ATF4, CHOP and XBP1s[56]
      BavachininFlavonoidThe liverHuman UGT1A1 enzymeInhibiting bilirubin metabolismUGT1A1[55]
      HepaRG cellsInducing oxidative stressP38, p-P38, JNK, p-JNK and ROS[57]
      IsobavachalconeFlavonoidThe liverHuman UGT1A1 enzymeInhibiting bilirubin metabolismUGT1A1[55]
      BakuchiolMonoterpene phenolThe kidneysHK-2 cellsWith obvious cytotoxicity[39]
      The liverMiceAltering the bile acid transport receptorNTCP[58]
      RatsInducing lipid metabolism disorderCYP7A1, HMG-CoA, BSEP, PPARα and SREBP-2[59]

      Table 2.  Characterization of the potential toxic compounds of PF

    • Jois et al. isolated and identified psoralen and isopsoralen from PF, which are considered as two main active components of PF [60, 61]. According to Chinese Pharmacopeia, their minimum total content in decoction pieces is 0.7% [1]. Modern pharmacological studies have shown that the coumarins of PF play a double role in pharmacological action and toxicity. XIA et al. found that the possible toxic substances were mainly rich in the ethyl acetate extract and the n-butanol extract, which are highly associated with the content of coumarins [62]. Moreover, other studies suggested that psoralen and isopsoralen had certain hepatotoxicity in zebrafish, mice and rats [63, 64]. The median lethal dose (LD50) of psoralen and isopsoralen in mice was 638.69 and 351.72 mg·kg−1, respectively [65]. On the other hand, two benzofuran glycosides of PF had potential hepatotoxicity. Psoralenoside and isopsoralenoside were rich in aqueous extract of PF and quickly absorbed into the circulation system, before being metabolized into excessive psoralen and isopsoralen in the gastrointestinal microenvironment, leading to liver injury [66].

    • Several flavonoids in PF exhibited stronger in vitro toxicity than coumarins, such as bavachin, bavachinin and isobavachalcone. Bavachin induced a significant increase in the production of reactive oxygen species (ROS), aggravating mitochondrial damage in HepG2 cells [67]. Bavachinin had strong cytotoxic effect on HepaRG cells, and the underlying mechanism was associated with oxidative damage via the p38/JNK MAPK pathways [57].

    • It was found that bakuchiol induced nephrotoxicity and hepatotoxicity [68]. Bakuchiol exhibited obvious toxicity to HK-2 cells, and its combination with psoralen aggravated cell damage [39]. With regard to hepatotoxicity, after treatment with bakuchiol at 52.5 mg·kg−1·d−1 for six weeks, the transaminase activities of rats were enahnced, and the expression of bile acid transporter-related proteins significantly changed [59]. Bakuchiol also inhibited the growth of HepG2 cells, with the half maximal inhibitory concentration (IC50) of 41.3 μmol·L−1 [69].

    Detoxification Methods
    • Compatibility is one of the most classical principles in TCM theories, with synergistic effect and detoxification compatibility. There are many PF-related prescriptions compatible with other herbs that have been recorded in TCM books and widely used in clinical applications. Common compatible herbs with PF include Myristicae Semen (MS), Juglandis Semen (JS), Eucommiae Cortex (EC), and Cistanches Herba (CH), etc. We summarized the combination effects and possible mechanisms involved (Table 3). The underlying detoxification mechanisms and profound connotation of classical prescriptions require further studies, which will help to reveal the key point of safe use of herbal combination.

      No.PF-herbal medicineExperimental modelDose of FP (raw drug)DurationCombination effectMechanismReference
      1 PF-Rehmanniae Radix Rats 4.05 g·kg−1 28 d Reducing hepatotoxicity Regulating body temperature and ATPase activity [70]
      2 PF-Epimedii Folium Rats 0.22 g·kg−1 1 d Increasing hepatotoxicity Inducing idiosyncratic hepatotoxicity under immunological stress conditions [71]
      3 PF-Paeoniae Radix Rubra
      Rats 3.75 g·kg−1 1 d Reducing hepatotoxicity Regulating arachidonic acid
      metabolism and glycerophospholipid metabolism pathways
      [36]
      4 PF-Glycyrrhizae Radix et Rhizoma Rats 40 g·kg−1 1 d Increasing renal toxicity The absorbance of bakuchiol increased, and its clearance was prolonged. [72]
      5 PF-Eucommiae Cortex Rats 0.68 g·kg−1 6 w Increasing bioactivity during treatment
      Menopausal syndrome
      Exerting the greatest estrogen-like effects [73]
      6 PF-Eucommiae Cortex Zebrafish 200 μmol·L−1 6 dpf Reducing toxicity The gene expression of immune activation and toxicity decreased. [74]
      7 PF-Cnidiic Fructus Mice 3.6 g·kg−1 6 w The inhibitory effect on mammary cancer metastasis to bone was enhanced Regulating OPG/RANKEL secretion ratio [75]

      Table 3.  The compatibility effects with PF and possible mechanisms

      The metabolic process of main ingredients of PF changes, during combined use with other medicines, while the pharmacokinetics parameters of some compositions also change (Table 4). TANG et al. simultaneously determined the multiple compounds of Xianling Gubao Capsules in a reversed pharmacodynamic-pharmacokinetics study, and found that coumarins and prenylated flavonoids from PF had high exposure and profiled the pharmacokinetic features of representative substances [76]. ZHAO et al. investigated the compatibility from the perspective of pharmacokinetics and drug metabolism, and found that glycyrrhetinic acid, one of the main components of Glycyrrhiza uralensis Fisch., might increase renal toxicity by inhibiting the metabolism of PF by CYP450 enzyme [72]. In addition, some studies focused on formula decomposition and toxicity comparison, and some representative components of PF were selected to preliminarily screen out the crucial compatible herbs and identify its composition and to explore the detoxification mechanism. NING et al. utilized an effective and high-sensitive model of zebrafish to screen the detoxification compatible medicines with PF, and found that EC exhibited the stronest effects on attenuating the toxicity of PF. Further studies revealed that the aucubin of EC reduced the hepatoxicity induced by psoralen, which were associated with the HIF-1 pathway, chemical carcinogenic pathway and glutathione metabolic pathway [74].

      Oral medicinest1/2 (h)Tmax (h)Cmax (mg·L−1)AUC0-t (mg·h·L−1)CL (h·L−1·kg−1)Reference
      PF extract
      Psoralen 2.67 ± 0.65 9.00 ± 1.67 3,970 ± 1.26 41,140 ± 16.20 0.02 ± 0.01 [79]
      Isopsoralen 2.97 ± 0.87 10.00 ±1.27 2,130 ± 0.82 25,310 ± 9.40 0.02 ± 0.01 [79]
      Psoralenoside 3.49 ± 0.45 2.58 ± 0.59 1,460 ± 0.24 12,010 ± 2.47 4.38 ± 1.02 [79]
      Isopsoralenoside 5.64 ± 3.13 2.58 ± 0.59 2,580 ± 1.60 16,820 ± 6.45 2.56 ± 0.88 [79]
      Psoralidin 25.15 ± 2.08 1.08 ± 0.88 1.09 ± 0.34 35.61 ± 1.31 191.33 ± 7.61 [80]
      Bavachin 24.89 ± 4.73 1.00 ± 0.61 2.71 ± 0.83 100.59 ± 28.66 74.15 ± 23.08 [80]
      Isobavachalcone 22.21 ± 6.15 2.00 ± 0.00 2.35 ± 0.44 75.96 ± 10.16 136.69 ± 35.11 [80]
      Neobavaisoflavone 8.88 ± 5.15 24.00 ± 0.00 3.63 ± 1.23 88.46 ± 18.40 140.67 ± 21.90 [80]
      Bakuchiol 10.22 ± 5.54 2.8 ± 1.10 395.73 ± 107.45 4,516 ± 516 7.18 ± 1.54 [81]
      PF combinated with other herbal medicines
      Psoralen (compatibility with Semen myristicae) 9.22 ± 2.44 9.33 ± 2.73 7.91 ± 1.34 130.92 ± 18.72 139.03 ± 25.96 [82]
      Psoralen (Sishen Wan) 4.28 ± 0.68 8.25 ± 0.71 7.85 ± 0.78 99.49 ± 16.58 200.42 ± 33.46 [83]
      Isopsoralen (compatibility with Semen myristicae) 11.40 ± 6.60 9.33 ± 2.73 3.89 ± 0.54 69.49 ± 9.05 25.85 ± 58.57 [82]
      Isopsoralen (Sishen Wan) 4.97 ± 1.25 8.25 ± 0.71 3.53 ± 0.62 49.23 ± 8.50 400.91 ± 82.75 [83]
      Bakuchiol (compatibility with Glycyrrhizae Radix et Rhizoma) 8.65 ± 4.24 3.6 ± 0.89 575.16 ± 148.90 6,067.24 ± 416.01 5.50 ± 1.03 [81]

      Table 4.  Pharmacokinetic parameters of compounds in PF

    • Processing is an equivalently important method to attenuate the toxicity of herbs, according to TCM theories. There are two traditional processing methods of PF, which were recorded in medical books and have been widely used nowadays, namely the alcohol soaking and water rinsing method and the salt processing method. The former originated from Lei’s Treatise on Processing of Drugs and is the oldest detoxification method of PF. Modern studies have found that the content of some ingredients decrease when they are soaked in alcohol, including psoralen, isopsoralen, psoralenoside and isopsoralenoside, while psoralenoside and isopsoralenoside are transformed into psoralen and isopsoralen when being steamed. About 50% of the toxic components can be reduced by this method, and more potential toxics of PF may be alcohol-soluble [77]. Recently, SONG et al. has used 3D cultured human liver organoids combined with high connotation imaging to evaluate the detoxification of PF processed products, and verified that the hepatoxicity of PF decreased by the alcohol soaking and water rinsing method [78]. With regard to the salt processing method, XIA et al. found that it obviously alleviated liver injury induced by PF [62]. It is also listed in Chinese Pharmacopoeia due to the enhanced efficacy of PF.

    Conclusions
    • PF has a long history of clinical application with good theraputic effect and has been widely used in many countries. However, little record about the toxicity of PF was found in ancient medical books, and PF is still excluded from the list of toxic herbs according to Chinese Parmacopoeia [1]. However, the prominent liver injury caused by PF has attracted much attention worldwide. It is urgent to clarify its toxic substances and hepatotoxic mechanism. Although some efforts have been devoted to the safety of PF, the onset events and toxic molecules remain unclear. Integrative multi-omics research, high-sensitive and high-throughput model, and computational chemistry methods will provide new insights into this topic. In this paper, we have presented a comprehensive summary of the botany, potential risks, toxic characteristics, underlying mechanisms and detoxification methods of PF. Systematic research of the relationship between the pharmacological effects and its toxicity will not only improve its safe use but also facilitate its drug development.

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