bubble_chart Content

Dutohmanspipe Fruit acid (aristolochic acid) is a common component found in plants of the Dutohmanspipe Fruit family and genus. It is the first nitro compound discovered in the plant kingdom. It was first extracted from Aristolochia clematitis by Frichhinger in 1851, its structural formula was determined by Pailer in 1956, and it was successfully synthesized chemically by Kupchan in 1965. There are six basic types of Dutohmanspipe Fruit acid in nature, namely Dutohmanspipe Fruit acid I, II, IIIa, III, IVa, and IV, with molecular formulas of C₁₇H₁₁O₇N, C₁₆H₉O₆N, C₁₅H₈O₇N, C₁₆H₁₀O₇N, C₁₆H₁₁O₈N, and C₁₇H₁₃O₈N(2).

Near the capital of Belgium, Brussels, the number of cases of interstitial nephritis surged after 1992, prompting an epidemiological investigation in the area. After excluding patients who had taken nephrotoxic drugs (such as antipyretics, analgesics, diuretics, non-steroidal anti-inflammatory drugs) or those with idiopathic renal failure, almost all other patients had normal kidney function before taking this weight-loss prescription. In fact, many people had taken this weight-loss prescription for years without health issues, but after the prescription was changed in 1990 to include Stephania Tetrandra and Magnolia Bark, cases of renal failure began to emerge. It was later confirmed that the kidney disease was caused by Dutohmanspipe Fruit acid(3).

After the Chinese herbal medicine nephropathy incident, the Belgian Ministry of Health estimated that at least 10,000 people had taken herbal medicines containing Dutohmanspipe Fruit acid in the early 1990s. Therefore, on March 14, 2000, they issued a notice advising all individuals who had taken Chinese medicinal preparations in the past decade to have their kidney function checked and requested the cooperation of physicians and pharmacists. In the UK, based on two cases where patients developed Chinese herbal medicine nephropathy requiring dialysis or kidney transplantation after taking Chinese medicinals containing Dutohmanspipe Fruit acid for eczema treatment, the sale and use of such herbs were banned on July 29, 1999. On June 9, 2000, the U.S. Food and Drug Administration (FDA), despite "not having received any reports of similar adverse events to date," ordered the cessation of import, manufacture, and sale of raw materials and finished products known or suspected to contain Dutohmanspipe Fruit acid (4). The plants suspected to contain Dutohmanspipe Fruit acid numbered over 70 species, involving all varieties of the Dutohmanspipe Fruit genus, Asarum genus, Japanese honeysuckle stem genus, Qingteng genus, Cocculus Root genus, Bat Gua genus, Clematis genus, Akebia Stem genus, and Aucklandia Root genus. Some of these were included merely due to slight name associations and did not actually contain Dutohmanspipe Fruit acid. The WHO also issued a similar warning in its drug bulletin on November 2, 2000 (5). Countries such as Spain, Austria, Egypt, Malaysia, the Philippines, and Japan followed suit, announcing bans or requiring physicians to exclude the above ingredients when prescribing. Furthermore, even Magnolia Bark, which had appeared in Belgian weight-loss prescriptions, was banned, leading from a ban on herbs containing Dutohmanspipe Fruit acid to a comprehensive ban on Chinese medicinals. Consequently, many scholars suggested renaming Chinese Herbs Nephropathy (CHN) to Aristolochic Acid Nephropathy (AAN), as the term Chinese herbal medicine nephropathy often raised concerns that Chinese herbal medicine could cause kidney disease (6-7).

There are possibly over 600 species of plants containing Dutohmanspipe Fruit acid components in nature, widely distributed in tropical and subtropical regions. In China, there are about 40 species, commonly used medicinal materials include Cocculus Root (the root of Cocculus Root A. fangchi), manshurian dutchman's pipe stem (the dried vine stem of Northeast Dutohmanspipe Fruit A. manshuriensis), Dutohmanspipe Fruit (the mature fruit of North Dutohmanspipe Fruit A. contorta or Dutohmanspipe Fruit A. debilis), Dutchmanspipe Vine is the above-ground vine part, and slender dutchman's pipe root is its dried root; other less commonly used medicinal materials include Hanzhong Stephania Tetrandra (the root of heterophyllous Dutohmanspipe Fruit A. heterophylla), Xungufeng (the root and rhizome of woolly Dutohmanspipe Fruit A. mollissima), Zhushalian (the tuber of A. cinnabaria), Guangxi Zhushalian (the tuber of A. tuberosa), Muping Dutohmanspipe Fruit (the root of A. moupinensis), etc.; and foreign commonly used herbs include Germany's clematis-like Dutohmanspipe Fruit (A. clematitis), America's serpent root Dutohmanspipe Fruit (A. serpentaria), Indian Dutohmanspipe Fruit (A. indica), tube-flowered Dutohmanspipe Fruit (A. tubiflora), ear-leaved Dutohmanspipe Fruit (A. tagala), etc. (8)

Since the Chinese Medicine Committee of the Department of Health proposed: "All Chinese medicinal manufacturers holding licenses for preparations containing Dutohmanspipe Fruit acid components should add warnings on labels, inserts, and outer boxes - long-term continuous use may cause side effects such as renal failure; and all drug licenses containing Dutohmanspipe Fruit acid components should be changed to prescription drugs." Subsequently, on November 4, 2003, the use of Cocculus Root, slender dutchman's pipe root, manshurian dutchman's pipe stem, Dutohmanspipe Fruit, and Dutchmanspipe Vine, five Chinese medicinal materials containing Dutohmanspipe Fruit acid, was banned, prohibiting their manufacture, import, and revoking their drug licenses (9-10). Domestically, the sale of Dutohmanspipe Fruit genus plants Cocculus Root (A. fangchi), manshurian dutchman's pipe stem (A. manshuriensis), Dutohmanspipe Fruit (A. contorta or bell A. debilis), Dutchmanspipe Vine is the above-ground vine part, and slender dutchman's pipe root is its dried root is prohibited.

Asarum genus plants contain only trace amounts of Dutohmanspipe Fruit acid, whether this content is sufficient to cause harm needs further discussion. The Chinese Medicine Committee of the Department of Health in 2004 (Document No. 0930000756) (9-11) stipulated the inspection specifications and methods for Asarum Chinese medicinal materials, changing the medicinal part of Asarum Chinese medicinal materials from the whole plant to the root, and only after passing the inspection according to the announced specifications and methods (referring to the 14th edition of the Japanese Pharmacopoeia Taiping Huimin Heji Jufang) can they be used for manufacturing and dispensing. Additionally, preparations containing Asarum must be manufactured by decocting with water; the finished product must pass the factory's established HPLC inspection method before it can be sold.

Research on the acid content of Dutohmanspipe Fruit in Asarum, Wu Tianshang (12) and Zhou (13) et al. utilized the liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry system [LC/(+)APCI/MS/MS] to detect the Dutohmanspipe Fruit acid content in nine traditional Asarum species Chinese medicinals (A. crispulatum, A. debils, A. forbesii, A. heterotropoides, A. himalaicum, A. ichangense, A. maximum, A. sieboldii). They found that all these Asarum species contain Dutohmanspipe Fruit acid I, with content ranging from 3.3 ng/mg (A. sieboldii) to 3376.9 ng/mg (A. crispulatum), while Dutohmanspipe Fruit acid II was not detected at all. The Dutohmanspipe Fruit acid content in Asarum ranged between 3.3-105.9 µg/g. In 2003, Japanese scholar Tomoko Kawamura (referenced by Wu Tianshang (12)) and others analyzed the Dutohmanspipe Fruit acid 1 and II in 52 species of Dutohmanspipe Fruit family plants (48 species of Asarum, 3 species of Dutohmanspipe Fruit, and 1 species of Saruma) using HPLC. Apart from finding that all Dutohmanspipe Fruit species plants contained Dutohmanspipe Fruit acid 1 and II, they also detected Dutohmanspipe Fruit acid 1 in 38 Asarum species plants, with 4 Asarum species plants simultaneously detecting Dutohmanspipe Fruit acid I and II, with higher content in the leaves than in the rhizomes. Additionally, Ying Xixiang (14) (2003) used HPLC to detect Dutohmanspipe Fruit acid in Asarum and other Chinese patent drugs, finding the Dutohmanspipe Fruit acid content in Asarum to be 0.0014%. Xie Zhaoming (15) (2003) used HPLC to determine the Dutohmanspipe Fruit acid content in three types of Asarum (North Asarum, Hanseong Asarum, and Hua Asarum) to be 9.8, 6.3, and 11.4 µg/g respectively. Zhan Shun'an used liquid chromatography-electrospray ionization ion trap mass spectrometry (LC-ES-ITMS), with detection limits of AAI 0.012 µg/ml and AAII 0.15 µg/ml, to measure the Asarum content. Other researchers include (30) Xie Zhaoming (15), (31) Lin Zhaogeng (16), Jiang Xu (17), Guan Wenqiu (18), Gao Jun (19), Ma Guoxiu (20), and Lu Fenling (21).

Risk Assessment of Asarum Medicinal Material

1. Daily Intake

The dosage of Asarum varies greatly, and the amount used each time is evaluated by @RISK 4.5 as (0.18, 28.207, 95.871), with the most likely dose being 28.207g.

2. Acid Content in the Whole Herb of Asarum and Dutohmanspipe Fruit

The content data is input into the analysis tool @RISK 4.5 risk analysis software for simulation, mainly using the Risk Triangular Mode, resulting in the most likely values (minimum, most likely, maximum) of (4.37, 16.67, 54.261) mg/g.

3. Risk Assessment

Based on the aforementioned data, the carcinogenic and non-carcinogenic toxicity identification procedures for Dutohmanspipe Fruit acid are conducted. It is classified as a carcinogenic substance (Group 1, Group 2A) (Note: Herbal remedies containing plant species of the genus Aristolochia are carcinogenic to humans (Group 1). Naturally occurring mixtures of aristolochic acids are probably carcinogenic to humans (Group 2A). However, according to the database, there are no carcinogenic slope data, nor any reference doses for adverse reactions. Only the TD50 (mg/kg/day) of 0.0141 was found in the database TCPD: The Carcinogenic Potency Database.

HIA = (C×IFR×Tr×Ab) / TD50

Target Hazard Quotient: [(Daily intake per kg per person) × (Toxin contamination concentration obtained through @risk statistics) × (Extraction rate) × (Absorption rate)] / acute RfD

The carcinogenic probability of Dutohmanspipe Fruit acid is input into the target hazard quotient, with the extraction rate and absorption rate set to 1. The calculated HIA is 0.051, which is less than 1, therefore no chronic health effects are expected to occur.

1. Chinese Pharmacopoeia Commission of the People's Republic of China: Pharmacopoeia of the People's Republic of China Part I (2005), Chemical Industry Press (Simple Chinese).
2. Ding Linsheng, Lou Fengchang: Chemical Constituents of Aristolochia Plants. Chinese Herbal Medicine 1983; 14(9): 40-48.
3. Vanherweghem JL, Depierreux M, Tielemans C, Abramowicz D, Dratwa M, Jadoul M, Richard C, Vandervelde D, Verbeelen D, Vanhaelen-Fastre R. Vanhaelen M. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993; 341: 387-391.
4. FDA/CFSAN. Aristolochic Acid–Letter to Health Care Professionals, FDA Concerned About Botanical Products, Including Dietary Supplements, Containing Aristolochic Acid. U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition Office of Nutritional Products, Labeling, and Dietary Supplements. 2000; May 31.
5. WHO. Aristolochic acid-warning concerning interstitial renal fibrosis. Pharmaceutical Newsletter. 2000; 2.
6. Zhang Xiaoming, Zheng Falei: Kidney Damage Caused by Dutohmanspipe Fruit Acid. Foreign Medical Sciences (Urology Division). 2000; 20(3): 101-103.
7. Hu Shilin, Xu Youling: The Internationalization of Chinese Medicinals from the Perspective of Dutohmanspipe Fruit Acid Issue. World Science and Technology. 2001; 3(2): 5-8.
8. Ding Linsheng, Lou Fengchang: Chemical Constituents of Aristolochia Plants. Chinese Herbal Medicine. 1983; 14(9): 40-48.
9. Department of Health, Executive Yuan. Announcement No. 0920002350, November 4, 2003.
10. Department of Health, Executive Yuan. Announcement No. 0920002349, November 4, 2003.
11. Department of Health, Executive Yuan. Announcement No. 0930000756, November 4, 2003.
12. Wu Tianshang, Lin Zhaogeng: Research and Review of Dutohmanspipe Fruit. National Research Institute of Chinese Medicine. 1995, pp. 175-178.
13. Ting-Ting Jong, Maw-Rong Lee, Shun-Sheng Hsiao, Jar-Lung Hsai, Tian-Shung Wu, Shu Tuan Chiang, Shao-Qing Cai. Analysis of Aristolochic Acid in Nine Sources of Xixin, a Traditional Chinese Medicine, by Liquid Chromatography/Atmospheric Pressure Chemical Ionization/Tandem Mass Spectrometry. Journal of Pharmaceutical and Biomedical Analysis. 2003; 33: 831-837.
14. Ying Xi Xiang, Yuan Chang Lu, Qu Xian Xi: Determination of the content of 11 Chinese medicinal materials and 3 Chinese patent drugs containing Dutohmanspipe Fruit acid. Journal of Traditional Chinese Medicine 2003; 30(5):404.
15. Xie Zhaoming, Li Shunxiang, Liao Hancheng: Determination of Dutohmanspipe Fruit Acid A in Asarum by HPLC. Central South Pharmacy 2003, 1(3):164
16. Lin Zhaogeng: Literature Survey on Chinese Medicinals Containing Dutohmanspipe Fruit Acid and Chinese Herbal Medicine Nephropathy, CCMP-92-CT-06, pp.71.
17. Jiang Xu, Wang Zhimin, You Lishuang, Dai Liping, Ding Guangzhi: RP2HPLC Determination of Dutohmanspipe Fruit Acid A in Slender Dutchman's Pipe Root and Asarum from Different Origins. China Journal of Chinese Materia Medica 2004; 29(5).
18. Guan Wenqiu, Li Xiaomeng, Xiao Jiashang: Reversible High-Performance Liquid Chromatography for Determination of Dutohmanspipe Fruit Acid in Asarum and Its Preparations. Chinese Journal of Drugs and Clinics 2005; 5(4): 283-284.
19. Gao Jun: Determination of Dutohmanspipe Fruit Acid A in Huaxin by High-Performance Liquid Chromatography.
20. Hao Xuliang, Ni Yan, Li Xianrong: HPLC Determination of Dutohmanspipe Fruit Acid in Asarum from Different Origins and Varieties. Chinese Traditional Patent Medicine 2006; 28(8).
21. Ma Guoxiu, Yu Yan, Zhang Lide, Sun Kefeng, Chen Yingping, Liu Guifang: Determination of Dutohmanspipe Fruit Acid A in Whole Plant and Root of Northern Asarum and Acute Toxicity Study in Mice. Chinese Archives of Traditional Chinese Medicine 2006; 24(6).
22. Lu Fenling, Qin Ling, Huang Kunsen, Lin Xiuzhen, Lin Yazi, Zhang Huaxuan, Zheng Shujing, Huang Qiuyu, Huang Chengyu, Lin Zhehui: Identification of Asarum-Containing Chinese Medicinal Preparations by High-Performance Liquid Chromatography. Annual Report of the Bureau of Food and Drug Analysis, Taiwan R.O.C. 2005; 23: 154-161.