Toxicological Risks of Chinese Herbs

Abstract

As traditional Chinese medicine (TCM) has become more popular there have been increasing concerns about safety and potential toxicity of the Chinese materia medica (CMM) comprising plants, animal parts and minerals. The potential toxicity of many CMM is well recognised in TCM and to reduce risks use of some herbs is restricted whilst specific processing methods have been developed to modify the activities/toxicity of others. However adverse reactions have been reported, many of these are due misuse or abuse of Chinese medicine. The main problem remains products adulterated with pharmaceuticals for weight loss or erectile dysfunction. But some herbs have narrow therapeutic ranges (e.g., Aconitum species) so toxic effects are frequently reported. Toxic effects from chronic or cumulative dosing are difficult to detect in the traditional setting and recent reports have demonstrated the health problems from Aristolochia species. Despite safety concerns, Chinese medicine appears to be relatively safe with comparatively few reports of adverse reactions compared with overall drug reports. The wealth of information in the Chinese literature needs to be more widely available. As TCM is widely used by patients, improved pharmacovigilance and pharmacoepidemiology can contribute valuable safety information, relevant to clinical use.

Key words

Chinese materia medica - toxicity - Aconitum - Aristolochia - Chinese herbal medicine - traditional Chinese medicine

References

• 1 Pharmacopoeia of the People's Republic of China, Vol 1. Beijing; Peoples Medical Publishing House 2005
• 2 Chan K. Chinese medicinal materials and their interface with Western medical concepts.  J Ethnopharmacol. 2005;  96 1-18
• 3 Wang J, Van der Heijden R, Spruit S, Hankermeier T, Chan K, Van der Greef J, Xu G, Wang M. Quality and safety of Chinese herbal medicines guided by a systems biology perspective.  J Ethnopharmacol. 2009;  126 31-41
• 4 Xu J, Yang Y. Traditional Chinese medicine in the Chinese health care system.  Health Policy. 2009;  90 133-139
• 5 Leung A Y. Traditional toxicity documentation of Chinese materia medica – an overview.  Toxicol Pathol. 2006;  34 319-326
• 6 Chan K. Some aspects of toxic contaminants in herbal medicines.  Chemosphere. 2003;  52 1361-1371
• 7 Xue C C, O'Brien K. Modalities of Chinese Medicine. Leung PC A Comprehensive Guide to Chinese Medicine. Singapore; World Scientific Publishing Co. Pte. Ltd. 2003: 25-26
• 8 Zhu Y-P. Chinese Materia Medica – Chemistry, pharmacology and applications. Amsterdam; Harwood Academic Publishers 1998: 28-29
• 9 Bensky D, Clavey S, Stoger E. Chinese herbal medicine – materia medica, 3rd edition. Seattle; Eastland Press Inc. 2004 714-715 732-733
• 10 Wong A, Chan C. Review of adverse events related to Chinese medicines in Hong Kong, July 2004-June 2005.  Public Health Epidemiol Bull. 2005;  14 45-51
• 11 Edwards I R, Aronson J K. Adverse drug reactions: definitions, diagnosis and management.  Lancet. 2000;  356 1255-1259
• 12 Reginster F, Jadoul M, van Ysersele de Strihou C. Chinese herbs nephropathy presentation, natural history and fate after transplantation.  Nephrol Dial Transplant. 1995;  10 157-160
• 13 Heinrich M, Chan J, Wanke S, Neinhuis C, Simmonds M. Local uses of Aristolochia species and content of nephrotoxic aristolochic acids 1 and 2 – a global assessment based on bibliographic sources.  J Ethnopharmacol. 2009;  125 108-144
• 14 Nortier J, Vanherweghem J L. For patients taking herbal therapy- lessons from aristolochic acid nephropathy.  Nephrol Dial Transplant. 2007;  22 1512-1517
• 15 CIOMS Working Group III .Good Safety Information Practices. Guidelines for Preparing Core Clinical Safety Information on Drugs. Geneva; WHO 1995
• 16 Liang J Q, Wang L S. General situation on toxicity researches.  Zhongguo Zhong Yao Za Zhi. 2000;  25 56-58
• 17 Wang Q, Li H, Zhang Z. Causes and countermeasures about adverse reactions of traditional Chinese medicine.  Zhong Yao Cai. 2001;  24 430-433
• 18 Song W. Adverse reactions of Chinese medicine.  Chin J Basic Med Tradit Chin Med. 2000;  9 66-68
• 19 Chen Y. Safety monitoring of traditional Chinese medicines in China. Pharmacovigilance of herbal medicine: current state and future directions.  Drug Safety. 2006;  29 352
• 20 Zeng Z-P, Jiang J-G. Analysis of the adverse reactions induced by natural product-derived drugs.  Br J Pharmacol. 2010;  159 1374-1391
• 21 Sin J, Chan C. Review of adverse events related to Chinese medicines in Hong Kong, January 2000-June 2004.  Public Health Epidemiol Bull. 2004;  13 60-66
• 22 Wong A, Chan C. Review of adverse events related to Chinese medicines in Hong Kong, July 2004-June 2005.  Public Health Epidemiol Bull. 2005;  14 45-51
• 23 Itoh S, Marutani K, Nishijima T, Matsuo S, Itabashi M. Liver injuries induced by herbal medicines, Sho-saiko-to (xiao-chai-hu-tang).  Dig Dis Sci. 1995;  40 1845-1848
• 24 Homma M, Oka K, Ikeshima K, Takahashi N, Niitsuma T, Fukuda T, Itoh H. Different effects of traditional Chinese medicines containing similar herbal constituents on prednisolone pharmacokinetics.  J Pharm Pharmacol. 1995;  47 687-692
• 25 Ohnishi N, Okada K, Yoshioka M, Kuroda K, Nagasawa K, Takara K, Yokoyama T. Studies on interactions between traditional herbal and western medicines, effects of Sho-saiko-to (Xiao-Cai-Hu-Tang) on the pharmacokinetics of carbamazepine in rats.  Biol Pharm Bull. 2002;  25 1461-1466
• 26 Davies E G, Pollock I, Steel H M. Chinese herbs for eczema.  Lancet. 1991;  336 177
• 27 Kane J A, Kane S P, Jain S. Hepatitis induced by traditional Chinese herbs; possible toxic components.  Gut. 1995;  36 146-147
• 28 Perharic L, Shaw D, Leon C, De Smet P A, Murray V S. Possible association of liver damage with the use of Chinese herbal medicine for skin disease.  Vet Hum Toxicol. 1995;  37 562-566
• 29 Pillans P I. Herbal medicine and toxic hepatitis.  NZ Med J. 1994;  107 432-433
• 30 Vautier G, Spiller R C. Safety of complementary medicines should be monitored.  BMJ. 1995;  311 633
• 31 Yoshida E, McLean C, Cheng E S, Blanc P D, Somberg K A, Ferrell L D, Lake J R. Chinese herbal medicine, fulminant hepatitis and liver transplantation.  Am J Gastroenterol. 1996;  19 2647-2648
• 32 Levi M, Guchelaar H-J, Woerdenbag H J, Zhu Y-P. Acute hepatitis in a patient using a Chinese herbal tea – a case report.  Pharm World Sci. 1998;  20 43-44
• 33 But P P- H, Tomlinson B, Lee K-L. Hepatitis related to the Chinese medicine Shou wu pian manufactured from Polygonum multiflorum.  Vet Hum Toxicol. 1996;  38 280-282
• 34 Park G J, Ngu J. Acute hepatitis induced by Shou wu pian, a herbal product derived from Polygonum multiflorum.  J Gastroenterol Hepatol. 2001;  16 115-117
• 35 Wong D R, Panis B, Hooymans P, De Smet P A, Rosias P P. Recurrent toxic hepatitis in a Caucasian girl related to the use of Shou-Wu-Pian, a Chinese herbal preparation.  J Pediatr Gastroenterol Nutr. 2005;  41 256-258
• 36 Mazzanti G, Battinelli L, Daniele C, Mastroianni C M, Lichtner M, Coletta S, Constantini S. New case of acute hepatitis following the consumption of Shou Wu Pian, a Chinese herbal product derived from Polygonum multiflorum.  Ann Intern Med. 2004;  140 W30
• 37 Cardenas A, Restrepo J, Sierra F, Correa G. Acute hepatitis due to Shen-Min.  J Clin Gastroenterol. 2006;  40 629-632
• 38 Vanherweghem L J. Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium (Chinese herbs nephropathy).  J Altern Complement Med. 1998;  4 9-13
• 39 Chan T Y K. Aconite poisoning.  Clin Toxicol. 2009;  47 279-285
• 40 Singhuber J, Zhu M, Prinz S, Kopp B. Aconitum in traditional Chinese medicine – a valuable drug or an unpredictable risk?.  J Ethnopharmacol. 2009;  126 18-30
• 41 Ma H Y, Liu X B, Li N, Yang M. Interaction of aconitine and glycyrrhizic acid by HPLC.  Shizhen Guoyi Guoyao. 2006;  17 208-209
• 42 Liu W, Song F, Liu Z, Liu S. The chemical study on combination taboo of Radix Aconiti and Pinellia Tuber.  Huaxue Tongbao. 2008;  71 435-438
• 43 Tomlinson B, Chan T Y K, Chan J, Critchley J, But P H. Toxicity of complementary therapies: an eastern perspective.  J Clin Pharmacol. 2000;  40 451-456
• 44 Kolev S T, Leman P, Kite G C, Stevenson P C, Shaw D. Toxicity following accidental ingestion of Aconitum-containing Chinese remedy.  Hum Exp Toxicol. 1996;  15 839-842
• 45 Obatomi D K, Bach P H. Biochemistry and toxicology of the diterpenoid glycoside atractyloside.  Food Chem Toxicol. 1998;  36 335-346
• 46 Nortier J L, Vanherweghem J L. Renal interstitial fibrosis and urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi).  Toxicology. 2002;  181 577-580
• 47 Pozdzik A A, Salmon I J, Debelle F D, Decaestecker D, Van Dend Branden C, Verbeelen D, Deschodt-Lanckman M M, Vanherweghem J-L, Nortier J L. Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation.  Kidney Int. 2008;  73 595-607
• 48 Lemy A, Wissing K M, Rorive S, Ziotta A, Roumeguere T, Muniz Martinez M C, Decaestecker C, Salmon I, Abramowicz D, Vanherweghem J L, Nortier J. Late onset of bladder urothelial carcinoma after kidney transplantation for end-stage arisotolochic acid nephropathy: a case series with 15-year follow up.  Am J Kid Dis. 2008;  51 471-477
• 49 Kessler D A. Cancer and herbs.  N Engl J Med. 2000;  342 1742-1743
• 50 International Agency for Research on Cancer (IARC) .Some traditional herbal medicines, some mycotoxins naphthalene and styrene. IARC Monographs on the Evaluation of Carcinogenic Risks of Chemical to Humans. Lyon, France; IARC 2002: 69-128
• 51 Grollman A P, Morrie Craig A, Ganey P E, Liu Y, Lowenfels A B, Nortier J L, Schaneberg B T, Stegelmeier B L. Aristolochic acid related exposures expert panel report. Available at. http://ntp.niehs.nih.gov/files/AAPanelReportBSciJustFinal_Rdtd.pdf Accessed March 31, 2010
• 52 Wu K M, Farrelly J, Upton R, Chen J. Complexities of the herbal nomenclature system in traditional Chinese medicine: lessons learnt from the misuse of Aristolochia-related species and the importance of the pharmaceutical name during botanical drug product development.  Phytomedicine. 2007;  14 273-279
• 53 Chen J, Chen T. Chinese medical herbology and pharmacology. California; Art of Medicine Press, Inc. 2001: 36-39
• 54 Haller C, Benowitz N. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.  N Engl J Med. 2000;  343 1833-1838
• 55 Shekelle P, Hardy M, Morton S, Maglione M, Mojica W, Suttorp M, Rhodes S, Jungvig L, Gagné J. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis.  JAMA. 2003;  289 1537-1545
• 56 Bjornsson E. Drug-induced liver injury: Hy's rule revisited.  Clin Pharmacol Ther. 2006;  79 521-528
• 57 Mattocks A R. Chemistry and toxicology of pyrrolizidine alkaloids. New York; Academic Press 1986
• 58 Larrey D, Vial T, Pauwels A, Castot A, Biour M, David M, Michel H. Hepatitis after germander (Teucrium chamaedrys) administration: another instance of herbal medicine hepatotoxicity.  Ann Intern Med. 1992;  117 129-132
• 59 Loeper J, Descatoire V, Letteron P, Moulis C, Degott C, Dansette P, Fau D. Hepatotoxicity of germander in mice.  Gastroenterology. 1994;  106 464-472
• 60 Zhou S, Koh H, Gao Y, Gong Z, Lee E. Herbal bioactivation: the good, the bad and the ugly.  Life Sci. 2004;  74 935-968
• 61 Anonymous. MHRA raises concerns about safety of Polygonum multiflorum. MHRA Press Release 28 April 2006. Available at. http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON2023635 Accessed March 31, 2010.
• 62 Zhang L, Yang X, Sun Z, Qu Y. Retrospective study of adverse events of Polygonum multiflorum and risk control.  Zhongguo Zhong Yao Za Zhi. 2009;  34 1724-1729
• 63 Zhang L, Yang X, Deng Y. Evaluation and consideration on safety information abroad of Polygonum multiflorum and its preparations.  Zhongguo Zhong Yao Za Zhi. 2009;  34 2414-2418
• 64 McRae C A, Agarwal K, Mutimer D, Bassendine M F. Hepatitis associated with Chinese herbs.  Eur J Gastroenterol Hepatol. 2002;  14 559-562
• 65 Melchart D, Linde K, Hager S, Shaw D, Bauer R, Weidenhammer W. Monitoring of liver enzymes in patients treated with traditional Chinese drugs.  Complement Ther Med. 1999;  7 208-216
• 66 Al-Khafaji M. Monitoring of liver enzymes in patients on Chinese medicine.  J Chin Med. 2000;  62 6-10
• 67 Shaw D. Aspects of Chinese herbal medicine with relation to their hepatotoxicity [thesis]. London; Kings College 2007
• 68 Lee C-H, Wang J-D, Chen P-C. Case-crossover study of hospitalisation for acute hepatitis in Chinese herb users.  J Gastroenterol Hepatol. 2008;  23 1549-1555
• 69 Mantani N, Kogure T, Sakai S, Goto H, Shibahara N, Kita T, Shimada Y, Terssawa K. Incidence and clinical features of liver injury related to Kampo (Japanese herbal) medicine in 2496 cases between 1979 and 1999: problems of the lymphocyte transformation test as a diagnositic method.  Phytomedicine. 2002;  9 280-287
• 70 Ikegami F, Sumino M, Fujii Y, Akiba T, Satoh T. Pharmacology and toxicology of Bupleurum root-containing Kampo medicines in clinical use.  Hum Exp Toxicol. 2006;  25 481-494
• 71 Akashi K, Shirahama M, Iwakiri R, Yoshimatsu H, Nagafuchi S, Hayashi J, Ishibashi H. Drug-induced allergic hepatitis caused by glycyrrhizin or extract of licorice root.  Acta Hepatol Jpn. 1988;  1633-1637
• 72 Sugiyama T, Sugaya T, Chia S. A case of drug-induced allergic hepatitis by glycyrrhizin.  Jap J Gastroenterol. 1992;  89 1633-1637
• 73 Klier B, Schimmer O. Microsomal metabolism of dictamnine: identification of metabolites and evaluation of their mutagenicity in Salmonella typhimurium.  Mutagenesis. 1999;  14 181-185
• 74 Bensoussan A, Myers S, Drew A, Whyte I, Dawson A. Development of a Chinese herbal medicine toxicology database.  Clin Toxicol. 2002;  40 159-167
• 75 Hsieh S-C, Lai J-N, Chen P-C, Chen H-J, Wang J-D. Development of active safety surveillance system for traditional Chinese medicine: an empirical study in treating climacteric women.  Pharmacoepidemiol Drug Saf. 2006;  15 889-899
• 76 Chen L C, Wang B R, Chu Y C, Tien J H. Drug utilization pattern of Chinese herbal medicines in a general hospital in Taiwan.  Pharmacoepidemiol Drug Saf. 2005;  14 651-657
• 77 Hsieh S-C, Lai J-N, Lee C-F, Hu F-C, Tseng W-L, Wang J-D. The prescribing of Chinese herbal products in Taiwan: a cross-sectional analysis of the national health insurance reimbursement database.  Pharmacoepidemiol Drug Saf. 2008;  17 609-619