European Review for Medical and Pharmacological Sciences 2017; 21 (1 Suppl): 46-52 Hepatotoxicity induced by greater celandine ( majus L.): a review of the literature

F. PANTANO1, G. MANNOCCHI1, E. MARINELLI1, S. GENTILI2, S. GRAZIANO2, F.P. BUSARDÒ1, N.M. DI LUCA3

1Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy 2Drug Abuse and Doping Unit, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy 3Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy

Flaminia Pantano and Giulio Mannocchi contributed equally to the manuscript

Abstract. – The available literature assessing Introduction L. (CM) hepatotoxicity poten- tial, and its risk to benefit assessment has been reviewed in this paper. Identification of signifi- Chelidonium majus L. (CM), also known as cant scientific literature was performed via the greater celandine, is a of the family Pa- following research databases: Cochrane Cen- paveraceae, which grows wild in part of Asia, tral, Google Scholar, EMBASE, Medline, Science Central and Southern Europe, in the Azores Direct, Scopus, Web of Science, using the fol- and North America1,2. It has been used for lowing keywords: “Chelidonium majus”, “great- a long time in hepatobiliary disorders: gall er celandine”, “Hepatotoxicity”, “Liver” “Inju- bladder and digestive dysfunctions; dyspeptic ry”, “Toxicity” individually investigated and then again in association. CM named also greater cel- complaints and spasms in phytotherapy and 3 andine, -wort, or bai-qu-cai (Chinese), traditional medicine . Currently, CM is widely has been used for a long time in traditional Chi- marketed on the websites of natural products as nese medicine and phytotherapy. Its extracts a remedy against several medical complaints. have been claimed to display a wide variety of bi- The plant contains quaternary and tertiary ben- ological activities: antimicrobial, anti-inflamma- zo[c]phenanthridine as major active tory, spasmolytic, antineoplastic, hepatoprotec- 4 tive, and analgesic. Moreover, components . Recently, numerous hepatotoxici- suggests this plant have numerous addition- ty reports have been suggested as linked with al effects which have not yet been scientifical- the use of herbal supplements containing CM5,6. ly evaluated, such as antitussive, diuretic, and However, the causal relationship between CM eye-regenerative. However, despite its claimed intake and the occurrence of liver damage has hepatoprotective effects, several hepatotoxici- not yet been fully established7. Animal studies ty cases have been reported to be probably or showed that the prolonged administration of highly probably connected with CM exposure, after their evaluation through liver-targeted cau- high doses of CM to rats did not determine liver sality assessment methods. CM hepatotoxicity damage, leading the authors to suggest to exclu- has been defined as a distinct form of herb-in- de an intrinsic plant toxicity8. Hence, it has been duced liver injury (HILI), due to an idiosyncrat- hypothesized that the harmfulness could have ic reaction of the metabolic type. This evidence been due to pharmacological interaction9-12. In has to be considered in relationship with the this concern, the most severe reactions have absence of considerable benefits of CM thera- py. Therefore, the risk to benefit ratio of the use been observed in subjects undergoing simulta- of herbal products containing greater celandine neous treatment with CM and hormones (estro- can actually be considered as negative. gens, thyroid hormones) and/or non-steroidal anti-inflammatory drugs (NSAIDs)13. The aim Key Words: of this paper was to review the available litera- Chelidonium majus L, Greater celandine, Hepato- ture assessing CM characteristics, risk to bene- toxicity, Liver, Injury, Toxicity. fit ratio and its hepatotoxicity potential.

46 Corresponding Author: Francesco Paolo Busardò, MD, MSc, DipFMS; e-mail: [email protected] Hepatotoxicity induced by greater celandine (Chelidonium majus L.): a review of the literature

Materials and Methods bladder) and on Kaposi’s sarcoma, as highlighted by human clinical studies21. The selection of appropriate scientific articles Also, CM action against inflammation has was performed through the following research been studied in animal models, demonstrating engines: Cochrane Central, Google Scholar, EM- that the methanol extract of this plant was able BASE, Medline, Science Direct, Scopus, Web of to inhibit the evolution of collagen-induced ar- Science, up to October 2016 using the following thritis in mice, decreasing the synthesis of certain keywords: “Chelidonium majus”, “greater celan- cytokines and modulating the amount of immune dine”, “Hepatotoxicity”, “Liver” “Injury”, “Toxi- cells and immunoglobulins22. Kokoska and colle- city”. The main keywords “Chelidonium majus” agues suggested that this herb could be one of the and “greater celandine” were searched individual- most active as an antimicrobial agent23. Choleretic ly and then in association with each of the others. activity has been studied on isolated perfused rat The 244 and 57 sources initially found respecti- livers, on which and phenolic fractions vely with “Chelidonium majus” and “greater ce- derived from CM and CM extract, determined landine”, were screened to exclude papers not su- a doubling of the amount of produced bile and a itable for the purpose of the review and duplicate reduction of bile acid concentration, after 40 mi- sources. Only 43 papers [1, 4, 7-8, 10, 13-50] (25 nutes24. The choleretic effect has also been stu- research articles, 8 case reports, 9 reviews and 1 died in humans, through the administration of a book) were included in the results. Moreover, a hydroethanolic extract intragastrically in healthy hand search was performed through the referen- patients and in subjects suffering from liver il- ces of the identified articles. lness. Bile flow was found to be increased25. Liver protection has been studied on rats, evaluating the defense from the toxicity due to carbon tetra- Results chloride, through the administration of a whole extract of CM in ethanol26,27. It has been shown CM Mechanism of Action that the previous treatment with CM was able to A huge number of studies have been develo- reduce the number of necrotic cells, the value of ped to assess CM efficacy in a large number of transaminases, bilirubin, and the fibrotic changes conditions, as this plant has been claimed to pro- due to carbon tetrachloride exposure. Also, the duce a wide variety of pharmacological effects1. hepatocarcinogenesis caused by p-dimethylami- Medicinal properties of CM can be attributed to noazobenzene was found to be antagonized by the alkaloids contained in the plant CM in mice28. Anti-ulcerogenic and gastropro- ( and aerial part). More than 27 components tective effects of CM extract have been evaluated have been described and divided into three main on gastric ulcers induced by indomethacin in rats. groups: a) benzo[c]phenanthridines, among which CM showed an action against the development of there are two subgroups -quaternary (chelerythri- ulcers, enhancing the release of prostaglandin E2 ne and ) and -tertiary like chelidoni- and decreasing leukotrienes29, and producing an ne; b) and derivatives such as allocryp- antispasmodic and analgesic activity as well. The topine; c) protoberberines (, )4. analgesic effect determined by its alkaloids was The plant contains flavonoids and phenolic acids similar to that of . The CM extracts pro- as well14. duced a relaxing and spasmolytic action on the Anticancer activity of CM has been observed abdominal and gastrointestinal muscles in animal in vitro studies. The plant constituents determine models, being able to reduce pain30,32. This effect cancer cell apoptosis and inhibition of mitosis15-17. was observed also in human clinical studies33. Specifically, Ukrain, a semi-synthetic alkaloid derived from CM, is characterized by antitumor, antineoplastic and immunomodulatory proper- CM Hepatotoxicity ties, determining dose and time dependent cyto- toxicity on cancer cell lines, among which those Animal Studies of breast cancer18,19. Moreover, these effects have Some studies on animal models have been de- been observed after the administration of the veloped in order to assess the defensive proper- whole extract of CM20. Ukrain, showed therapeu- ties of CM constituents or their ability to enhance tic effects with low adverse reactions on various the toxicity of other molecules. The protective kinds of cancer (colorectal, breast, pancreatic, potential of , the major active compo-

47 F. Pantano, G. Mannocchi, E. Marinelli, S. Gentili, S. Graziano, F.P. Busardò, N.M. di Luca nent of Chelidonium majus, and of its poly lacti- was studied in liver mitochondria of male albino de-co-glycolide (PLGA) poly incapsulated nano- mice4. The molecules showing greater inhibition form (nano-chelidonine), has been evaluated in strength in mitochondrial respiration were tho- the oxidative stress and hepatic toxicity induced se containing a positive charge, for the presence 34 by cadmium chloride (CdCl2) in mice . The study in their structure of a quaternary nitrogen atom: results showed that the exposure to CdCl2 for 30 , sanguinarine, berberine and copti- days (twice a week at the following dosage: 1.0 sine. The uncharged CM constituents underwent mg/kg body weight i.p.) caused oxidative stress more troubles in passing through the mitochon- through lipid peroxidation and accumulation of re- drial membrane. Berberine, was the most biologi- active oxygen species (ROS). The administration cally active alkaloid tested, and for this reason, it of nano-chelidonine after CdCl2 exposure mar- should display the highest toxicity. Moreover, the kedly diminished lipid peroxidation and oxidati- effects of chelidonine, coptisine, chelerythrine, ve stress and restored GSH (glutathione) levels. and sanguinarine were studied on oxidative pho- Therefore, nano-chelidonine was suggested as a sphorylation and calcium accumulation in rat li- protective agent, in mice, against cadmium toxici- ver mitochondria38. Chelerythrine and sanguina- ty. Also, the ability of CM to enhance the hepatic rine determined a block of the absorption and the effects of acetaminophen at a sub-toxic dose was accumulation of calcium cations and repressed evaluated in rats7. If administered alone, CM did oxidative phosphorylation, while chelidonine did not modify liver parameters in male rats while in not influence the studied parameters. The effects female animals a rise of fibrinogen levels was ob- observed on mitochondria are directly connected served. No changes in hepatic histomorphology to DNA intercalating properties, as sanguinarine were noticed in both sexes. Liver alterations were and chelerythrine are strong intercalators, while observed after the administration of sub-toxic do- chelidonine is not. Finally, after oral administra- ses of acetaminophen, while the co-administra- tion of CM on Wistar rats for two or four weeks, tion of CM did not enhance hepatotoxic effects. at the following dosage: 1.5-3 g/(kg day) (this Additionally, the anti-tumor properties of CM amount should be considered 50-100 times higher and its modulation of enzyme activity in the liver than that generally consumed by humans), no sub- have been studied administering a homeopathic stantial change was noticed in animals, regarding extract (in micro doses Ch-30 and Ch-200) of CM to: body weight, food intake, enzyme activities to mice, during hepatocarcinogenesis induced by and liver histomorphology. Nevertheless, a mild p-DAB (p-dimethylaminoazobenzene) compared but significant reduction of GSH levels, as well as to control groups35. All mice that were admini- superoxide dismutase (SOD) activity was obser- stered p-DAB developed liver tumors. Approxi- ved. Therefore, these mild alterations suggest par- mately the 40% of the animals in which p-DAB ticular caution in administering CM in conditions was administered in association with Chelido- characterized by an impairment of liver function8. nium, did not develop liver tumors. Chelidonium homeopathic medicine showed an anti-tumor ef- Human Hepatotoxicity Reports fect and an anti-genotoxic activity and favorably The liver damage due to herbal remedies is also modulated the effects of certain enzyme markers. named: herb-induced liver injury (HILI). The lat- Moreover, the inhibition potency of CM alkaloids ter represents a rare occurrence that follows the on several enzymes was tested in animal stu- exposure in a small amount of susceptible indivi- dies. Chelidonine, berberine, sanguinarine, and duals39-41. HILI features are comparable to those “Ukrain” (a semisynthetic drug derived from CM) of drug-induced liver injury (DILI). While per- displayed an irreversible inhibition of serotonin forming causality assessment, it is of primary im- and tyramine oxidative deamination reaction, portance to choose the proper evaluation method. in rat livers mitochondrial monoamine oxidase Teschke and Danan stressed the concept that cau- (MAO)36. However, the same metabolic pathway sality assessment in HILI suspected cases should was not blocked for the substrate benzylamine. be performed through the Council for International This finding suggests that mainly oxidative dea- Organizations of Medical Sciences scale (CIOMS), mination performed by MAO form A is blocked also known as Roussel Uclaf Causality Assessment by CM alkaloids. Ukrain and chelidonine showed Method (RUCAM) which is an instrument valida- the strongest inhibition potency, while sanguina- ted for hepatotoxicity and specific for the liver42. rine and berberine exhibited a weaker action37. Si- Liver damage due to CM intake in humans milarly, the inhibition potential of CM alkaloids, has been mainly supported by case reports and

48 Hepatotoxicity induced by greater celandine (Chelidonium majus L.): a review of the literature reviews that evaluated the cases reported in and the hepatic functions were found to be nor- scientific papers and spontaneous signaled ad- mal within two months. Two cases of acute liver verse reactions. The onset of haemolytic anae- damage connected with the use of CM where mia due to the oral ingestion of CM extract was also reported in 200347. In both patients, other firstly observed in 1990 and was characterized culprits of acute liver injury were excluded, in by intravascular haemolysis, thrombocytope- order to assess causality. A recurrence of chole- nia, renal failure and liver cytolysis43. The pa- static hepatitis after CM re-exposure occurred tient underwent treatment with steroids, blood in one patient. The two patients recovered fully, components, transfusion and with haemodialy- but the authors highlight the fact that the autho- sis twice. The 12th-day complete resolution of rization of CM administration should be recon- the clinical features was observed. Similarly, a sidered, as actually there is a lack of therapeutic 42-year-old woman was admitted to the hospital benefits connected with this drug. Another case because of the reappearance of acute hepatitis of regards a 58-year-old man admitted with acute uncertain origin44. Her past clinical history was cholestatic hepatitis after the use of a CM pre- characterized by alanine transaminase (ALT) paration48. Histopathology showed a picture of elevation (concentration of 755 U/l), preceded drug-induced hepatitis however after disconti- by the intake of herbal remedies as an alterna- nuation of the herbal product the patient recove- tive medication, including common (or lesser) red fully. A further case of liver damage was de- celandine. ALT maximum values during the scribed in 2008, involving a woman admitted to hospitalization were 350 U/l. All other possible the hospital for asthenia, nausea, anorexia and causes of hepatitis, such as viral infection, meta- with deranged liver enzymes49. She was found bolic diseases, and autoimmune aetiology were to have used a Lycopodium similiaplex prepara- excluded. Liver biopsy showed an acute necroti- tion (containing Lycopodium serratum and Che- zing hepatitis. Treatment was performed mainly lidonium majus) for 8 weeks before the onset through the avoidance of re-exposure and liver of symptoms. Liver biopsy was suggestive of a enzymes returned normal. Concordantly, ten hypersensitivity reaction and concordantly with cases of acute hepatitis connected with the in- the other reports she fully recovered. Teschke et take of CM preparations were noticed from al10 evaluated the connection between CM inta- 1997 until 1999 in Germany13. The evolution of ke and hepatotoxicity in 21 published case re- liver impairment in these patients was mild to ports, using a causality evaluation method spe- severe. In half of the cases, important cholesta- cific for the liver, as a multitude of confounding sis was detected, but was not followed by liver variables might have misled causality. For this failure. Other potential sources of liver dama- reason, all 21 cases were examined through the ge such as secondary biliary, alcoholic dama- CIOMS scale, which considers: risk factors, the ge, viral hepatitis, hereditary and autoimmune latency period, comedication and other alterna- conditions were excluded performing imaging tive causes, the trend of ALT after drug with- procedures, laboratory tests and liver biopsies. drawal. The results showed a high probability These last were compatible with damage indu- of causality in two cases out of 21. Probable in ced by drugs. The discontinuation of CM intake six cases. Lower causality levels were found in determined rapid recovery in patients and the the remaining cases in which the causality was level of liver enzymes returned normal in 2-6 excluded for three patients and recognized as months. Unintentional re-exposure determined possible in 10 cases. Regarding the 8 probable recurrence of hepatitis in one patient, this fact, events, hepatotoxicity due to CM embodies an is the most appropriate criterion for HILI cau- idiosyncratic reaction of the metabolic kind, sality assessment45. In conclusion, a great per- while immunologic or mandatory hepatotoxic centage of unsolved cases of hepatitis could be characteristics are missing. Therefore, an ac- related to CM. Moreover, the manifestation of curate search and identification of confounding jaundice related to acute hepatitis was observed variables should be performed while evaluating in a 42-year-old woman, several weeks after the the cases, but there is striking evidence for HILI consumption a herbal remedy containing CM due to GC in the cases analyzed by the authors. and curcuma root, which she took for a skin Moreover, the same author evaluated 22 spon- illness46. In accordance with the cases repor- taneous cases from Germany attributing to 8 ted above, clinical conditions improved rapidly events, a highly probable or probable causality after the discontinuation of the herbal product assessment, with a predominance for the female

49 F. Pantano, G. Mannocchi, E. Marinelli, S. Gentili, S. Graziano, F.P. Busardò, N.M. di Luca gender50. All patients recovered. Taken together, Conflict of interest the above-reported case reports actually support The authors declare no conflicts of interest. the hepatotoxic potential of CM preparations. References Conclusions 1) Gilca M, Gaman L, Panait E, Stoian I, Atanasiu V. An abundant number of herbal remedies has Chelidonium majus--an integrative review: tradi- been suggested to be linked with the risk of li- tional knowledge versus modern findings. Forsch Komplementmed 2010; 17: 241-248. ver damage, this side effect, as well as others, Kadan G, Gözler T, Shamma M. must be clearly underlined, in the light of an 2) (−)-Turkiyenine, a 51 new alkaloid from Chelidonium majus. J Nat Prod increase of popularity of herbal preparations . 1990; 53: 531-532. Moreover, the clinical effectiveness of these 3) Barnes J, Anderson LA, Phillipson JD. Celandine, remedies is frequently only supposed and does greater. Herbal medicines. Pharmaceutical Press, not seem to counterbalance the potential risks. 2007. Although important evidence of hepatotoxicity 4) Barreto MC, Pinto RE, Arrabaca JD, Pavão ML. Inhi- in animal studies is still not well defined, CM bition of mouse liver respiration by Chelidonium extracts and constituents displayed alterations majus isoquinoline alkaloids. Toxicology Letters 2003; 146: 37-47. and inhibition of liver metabolism suggestive 5) Tarantino G, Pezzullo MG, Di Minno MN, Milone for hepatotoxic potential. Numerous reports F, Pezzullo LS, Milone M, Capone D. Drug-indu- have been published about hepatotoxicity cases ced liver injury due to “natural products” used for following CM intake, and several of them have weight loss: a case report. World J Gastroenterol been reported to be connected with CM expo- 2009; 15: 2414-2417. sure with probability or high probability. Liver 6) Teschke R, Glass X, Schulze J. Herbal hepatotoxi- histology, when available, showed: liver cell city by Greater Celandine (Chelidonium majus): necrosis (single or confluent), inflammation and causality assessment of 22 spontaneous reports. Regul Toxicol Pharmacol 2011; 61: 282-291. more seldom cholestasis and fibrosis52. CM he- 7) Mazzanti G, Di Sotto A, Di Giacomo S, Durazzi F, patotoxicity has been defined as a distinct form Mariani P, Nicoletti M, Mammola CL, Vitalone A. of HILI, due to an idiosyncratic reaction of the Chelidonium majus L. does not potentiate the he- metabolic type. This fact has to be evaluated in patic effect of acetaminophen. Exp Toxicol Pathol relationship with the lack of substantial benefits 2013; 65: 1117-1120. due to the therapy with CM. For these reasons, 8) Mazzanti G, Di Sotto A, Franchitto A, Mammola CL, currently, the risk to benefit ratio of the use of Mariani P, Mastrangelo S, Menniti-Ippolito F, Vita- lone A herbal products containing CM can be consi- . Chelidonium majus is not hepatotoxic in Wistar rats, in a 4 weeks feeding experiment. J dered as negative, although the described he- Ethnopharmacol 2009; 126: 518-524. patotoxicity has generally manifested a benign 9) Moro PA, Cassetti F, Giugliano G, Falce MT, Maz- course with the recovery of the patients after zanti G, Menniti-Ippolito F, Raschetti R, Santuccio C. discontinuation of the intake. Hepatitis from Greater celandine (Chelidonium majus L.): review of literature and report of a new case. J Ethnopharmacol 2009; 124: 328-332. Authors’ contributions 10) Teschke R, Glass X, Schulze J, Eickhoff A. Suspected Greater Celandine hepatotoxicity: liver-specific cau- All the authors made substantial contributions to sality evaluation of published case reports from Euro- conception and design of the manuscript; GM, FP pe. Eur J Gastroenterol Hepatol 2012; 24: 270-280. and SG performed the literature search and NML, 11) Williamson EM. Drug interactions between herbal FPB and SG revised it. All the authors have been and prescription medicines. Drug Saf 2003; 26: involved in drafting the manuscript and revising 1075-1092. it critically for important intellectual content and 12) Olesen C, Harbig P, Barat I, Damsgaard EM. Absence all of them have given final approval to the ver- of ‘over-the-counter’ medicinal products in on-line sion to be published. prescription records: a risk factor of overlooking interactions in the elderly. Pharmacoepidemiol Drug Saf 2013; 22: 145-150. 13) Benninger J, Schneider HT, Schuppan D, Kirchner T, Acknowledgements Hahn EG. Acute hepatitis induced by greater ce- The authors thank Michele Sciotti for technical landine (Chelidonium majus). Gastroenterology assistance in manuscript preparation. 1999; 117: 1234-1237.

50 Hepatotoxicity induced by greater celandine (Chelidonium majus L.): a review of the literature

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