Yuan Yao,Gen-Bei Wang,Shu-Li Man＊,Long Ma,Wen-Yuan Gao

1State Key Laboratory of Food Nutrition and Safety,Key Laboratory of Industrial Microbiology,Ministry of Education,Tianjin Key Laboratory of Industry Microbiology,China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry,College of Biotechnology,Tianjin University of Science & Technology,Tianjin 300457,China; 2Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency,School of Pharmaceutical Science and Technology,Tianjin University,Tianjin 300072,China; 3State Key Laboratory of Core Technology in Innovative Chinese Medicine,Tasly Academy,Tasly Holding Group Co.,Ltd.,Tianjin 300410,China.

Abstract

Keywords: Traditional medicine (TM),Natural product,Herb,Toxicity,Toxic target organs,Risk assessment,Safety evaluation

Background

Safety,effectiveness and quality control belong to three basic characteristics of drug.During 2019,there were a number of papers referred to the safety assessment of toxins [1] like metal [2],elemental distribution [3],toxic proteins [4,5] and special secondary metabolites in traditional medicine (TM),which might be also the bioactivation of herbal constituents [6].The herbs includedCuscuta chinensis Lamepithymum [7],Cassiae semen[8],Ephedra sinica Stapf[9],MeLia toosendan Sieb.et Zucc.[10],Psoralea corylifolia Linn.[11],Gynura segetum(Lour.)Merr.[12],Leonurus artemisia(Laur.)S.Y.Hu F[13],Polygonum multiflorum[14-16],Tripterygium wilfordii Hook.f.[17,18],Telfaria occidentalisroot[19,20] and so forth.At the same time,people paid attention to different age groups such as infants [2],children [21-23],adults [24],pregnancy and the postnatal period [13,25-27] in the use of TM.Liquid Chinese patent drug,especial for injection received researchers’ more attention like Xiyanping injection[28],Tianfoshen oral liquid [29],and motherwort injection [13].New detection technology like multispectral optoacoustic tomography (MSOT)imaging the precise location of herbal-medicine-induced liver injury with 3D information in a noninvasive way using conjugated-polymer-based ratiometric nanoprobe was applied [14].A computational toxicology approach was also applied to screening the hepatotoxic ingredients in TM [15].Furthermore,China played the key role in the promotion of the rapid upsurge in this field.Statistical analysis of annual publications of toxicological studies on TM by relative percentages on different countries is showed in Figure1.USA ranked the second important countries,while India was tied with Canada and Brazil ranked the third place researching the toxicology of TM.In addition,compared to 2018,many counties like Australia,Germany and UK started to pay attention to the safety evaluation of TM.

Organ toxicity

Liver is regarded as the top 1 toxic target organ in TM

Liver is the most important organ of drug metabolism and detoxification in the body.For herb-induced liver injury was a growing clinical and economic problem worldwide,there were a large amount of researches focusing on liver toxicity in 2019.For example,new detection technologies like MSOT imaging the precise location ofFallopiamultiflora(Thunb.)Harald-induced liver injury with 3D information was applied due to oxidative/nitrosative stress resulted from hepatically-generated reactive oxygen species/reactive nitrogen species[14].A computational toxicology approach was applied to screening the hepatotoxic ingredients inFallopia multiflora(Thunb.)Harald[15].Integrating serum exosomal microRNA and liver microRNA profiles were used to disclose the mechanism ofMeLia toosendan Sieb.et Zucc.-induced hepatotoxicity in mice [10].Meanwhile,metabolism was used commonly to display cholestatic liver injury caused by psoralen [30],isopsoralen [30] andGynura segetum(Lour.) [12],and metabolic disorder like glycerophospholipid metabolism,primary bile acid biosynthesis,sphingolipid metabolism,phenylalanine,tyrosine and tryptophan biosynthesis,and tyrosine metabolism byDaphne genkwa Sieb.et Zucc.[31],Glycyrrhiza uralensis Fisch.[31],Sophora flavescens Ait.[32]andXysmalobium undulatum[33].

Kidney is considered as the second toxic target organ in TM

Renal blood flow is abundant,accounting for 25% of cardiac output,so a large number of drugs can reach the kidney with blood flow to cause pathological changes.For example,aristolochic acid I was recognized as the major cause of aristolochic acid nephropathy before [34].During 2019,untargeted liquid chromatograph-mass spectrometer-based metabonomics was used to reveal that aristolochic acid I inhibited amino acids metabolism,glucose metabolism,beta-oxidation of fatty acids and the tricarboxylic acid cycle in male mice[35].Aristolochic acid I could also react with genomic DNA to form persistent DNA adducts with purines to induced nephrotoxicity [36].Chemotherapy usually induced nephrotoxicity like cisplatin[37]and doxorubicin[38].In the year of 2019,researchers reported that grape pomace extract did not protect against cisplatin-induced nephrotoxicity,but accentuated the toxic effect of cisplatin [37].Dioscorea bulbiferaL.delayed the excretion of doxorubicin and accumulated doxorubicin in the body,which was associated with its inhibition of P-glycoprotein in liver and kidneys [38].Furthermore,it was reported that the incompatible herb pairEuphorbia kansui T.N.Liou ex S.B.HoandGlycyrrhiza uralensis Fisch.induced hepatotoxicity and nephrotoxicity and attenuated the effect of Gansui Banxia decoction[39].

Other toxic target organs of TM

In 2019,a review introduced poisoning by toxic plants in Hong Kong.62 cases involving 26 poisonous plant species were identified,among which Alocasia macrorrhizos (Giant Alocasia),Gelsemium elegans(Graceful Jessamine),and Rhododendron (Azalea)species were the three most commonly encountered.Gastrointestinal toxicity (n = 30,48%),neurological toxicity(n=22,35%),and hepatotoxicity(n=6,10%)were the three most common clinical problems.Forty-nine (79%) and eight (13%) patients had mild and moderate toxicity,respectively.They were all recovered shortly with supportive treatment.The remaining five (8%) patients experienced severe toxicity requiring intensive care support[40].

Meanwhile,the mechanisms of reproductive injuries induced by combination ofDaphne genkwa Sieb.et Zucc.andGlycyrrhiza uralensis Fisch.[31],cardiotoxicity and neurotoxicity caused by diester and monoester diterpenoid alkaloids in processedAconitum carmichaeli Debx.root [41],cardiotoxicity induced byChloranthus serratus[42],gastrointestinal injury incurred byGardenia jasminoides Ellis[43] and so forth were explained in 2019.These extracts should be used with caution.Taken together,statistical analysis of annual publication referred to different toxic target organs induced by TM is summarized in Figure2.

Current advances

Zebrafish embryoes are popular for evaluating the safety of TM

Right now,the safety evaluation has been applied in cellular,organ & individual levels.Rodents are regarded as the common individual models to analyze the safety of TM or natural products.Meanwhile,zebrafish embryoes are secondly widely used because of its rapid,medium throughput and cost-effective.During 2019,it was used to evaluate the liver protection and hepatotoxicity of saikosaponin a [44],aloe emodin [45],and triptolide [46],teratogenicity ofMomordica charantiaseeds and fruits [47],heart toxicity of Libidibia ferrea (juca) [48],reproductive toxicity ofEndopleura uchi(Huber)Cuatrec[49] and so forth.Although caenorhabditis elegans [50] and drosophila [51] were popular in the safety evaluation of various chemical compounds recently,there were no relative research in TM in 2019.

Figure1 Statistical analysis of annual publications on toxicological studies on TM by relative percentages on different countries.TM,traditional medicine.

Figure2 Statistical analyses of annual publications on toxicological studies on TM by relative percentages on different toxic target organs.TM,traditional medicine.

Safety evaluation of TM in different kinds of people

Recently,safety medication has been concerned to different kinds of people,such as infants [2],children[21-23],adults [24] and maternal [13,25-27].During 2019,a review reported the safety of the herbal medicinal product used during pregnancy and postnatal period [25].In this report,almond oil might induce preterm birth,the use of oral raspberry leaf was related to cesarean delivery; the application of heavy licorice use was relative to early preterm birth by 3.07-fold.African herbal medicine mwanaphepo was also reported to be associated with maternal morbidity,neonatal death or morbidity [25].Meanwhile,other research reported thatAnastatica hierochunticaaqueous extract [26] and Snus tobacco [27] displayed potential toxicity during pregnancy.What’s more,it attracted attention to the safety assessment of toxic metals in commonly used pharmaceutical herbal products in Jordanian market [2],a mixed extract containing marshmallow root,chamomile flowers,horsetail herb,walnut leaves,yarrow herb,oak bark and dandelion herb in the treatment of acute non-bacterial tonsillitis [21],and green tea [22] in children.

New toxicology study technology

In 2019,new technology was used in toxicology evaluation.For example,a computational toxicology approach was also applied to screening the hepatotoxic ingredients in TM [15].Electrospray laser desorption ionization mass spectrometry was used to rapid identify herbal toxins [1].MSOT imaging conjugated with polymer-based ratiometric nanoprobe was applied for the precise location of TM-induced liver injury with 3D information in a noninvasive way [14].Furthermore,integrating serum exosomal microRNA and liver microRNA profiles were used to disclose the mechanism of TM-induced hepatotoxicity in mice[10].

Conclusion

Taken together,the annual research shows that liver,kidney and heart are the mainly toxic target organs of TM.Their toxic mechanisms include cell apoptosis,metabolic disorder,oxidative stress,inflammatory damage,liver and renal fibrosis and even inducing carcinogenesis.Safety medication of TM has been concerned to different kinds of people,such as infants,children and maternal.Besides rodents,zebrafish embryoes have been regarded as common models to evaluate the safety of TM.New technologies in toxicology focus on how to screen and identify toxin in TM,how to image the precise location of TM-induced tissue injury with 3D information,and how to explain the mechanism of TM-induced toxicity.In the future,study on the toxicity mechanism of other target organs,drug safety in elders,new models and methods should be used in the prevention of TM toxicology.