Aristolochic acids

Aristolochic acids are a group of organic compounds that occur naturally in plants of the genera Aristolochia and Asarum. These acids are known for their toxic and carcinogenic properties, but have a long history in traditional medicine, especially in China, where they were used in herbal medicine. Due to the serious health risks, aristolochic acids are today banned in many countries or strictly regulated.

Applications in traditional medicine

In traditional Chinese medicine (TCM), Aristolochia species were historically used for a wide variety of ailments. Some of these effects have also been examined in studies, which are cited here; however, research on aristolochic acid focuses rather on its toxicological properties. Here are some of the benefits that have been attributed to aristolochic acid or the plants.

  • Pain relief: for the treatment of rheumatic pain and swelling (1,2).
  • Inhibition of inflammation: For respiratory diseases and arthritis (2)
  • Promotion of menstrual flow: in women with menstrual complaints.

Properties and chemical structure

Aristolochic acids belong to the class of nitrobenzyl carboxylic acids. They consist of an aromatic nitro group and a carboxyl group. The most important representatives are aristolochic acid I and II, which differ slightly in their chemical structure. These compounds are able to interact with DNA and form covalent adducts, which can lead to mutations and potentially to the development of cancer.

Mechanism of action

The harmful effects of aristolochic acids are based on their ability to cause DNA damage. The mechanism comprises the following steps (3,4):

  1. Bioactivation: Aristolochic acids are converted into reactive metabolites in the kidneys.
  2. DNA adduct formation: These metabolites bind covalently to DNA, producing mutagenic DNA adducts.
  3. Mutations: The resulting mutations can inactivate tumor suppressor genes such as TP53, which promotes the development of cancer.

This mechanism explains why aristolochic acids are associated with certain types of cancer.

Health risks and side effects

Aristolochic acids are highly toxic and have been linked to serious diseases in several scientific studies:

  1. Aristolochic acid nephropathy (AAN): A specific form of kidney damage that frequently leads to chronic kidney failure.
  2. Cancer: The carcinogenic properties of aristolochic acids are well documented. Urothelial carcinoma, a malignant tumor of the urinary tract, is particularly common.
  3. Acute toxicity: Symptoms such as nausea, vomiting, abdominal pain, and liver damage can occur with short-term intake.

Because of these risks, the World Health Organization (WHO) has strongly criticized the use of Aristolochia species in medicine, and their use is prohibited in many places.

Research and science

Scientific research on aristolochic acids concentrates on their toxicological properties and on demonstrating their effects on human health:

  • Molecular studies: They show the formation of aristolochic acid-DNA adducts, which can be used as biomarkers for exposure and risk.
  • Epidemiological studies: They have found a close link between preparations containing Aristolochia and increased rates of kidney cancer in certain regions, especially in Asia and the Balkans (5,6,7).

Regulatory measures

Aristolochic acids are banned in many countries, including:

  • EU: The European Union has prohibited the sale and use of products containing aristolochic acids since 2001.
  • USA: The FDA warns against taking dietary supplements that contain Aristolochia species.
  • China: Although Aristolochia was widely used in TCM, many applications have been discontinued or replaced due to its toxicity.

Conclusion

Aristolochic acids are poisonous, carcinogenic substances that occur in certain plants and were historically used in traditional medicine. Because of their serious health risks, including kidney damage and cancer, they have been banned in many countries. Modern research has clearly documented the dangers of these compounds, so their use in medicine is no longer justifiable.

Sources

  1. Veale, E. L., & Mathie, A. (2016). Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels. British journal of pharmacology, 173(10), 1639–1652. https://doi.org/10.1111/bph.13465
  2. Nan Mei, Jiekun Xuan, Tao Chen, Baitang Ning, Lei Guo,Chapter 20 - Gene Expression Profiling in Evaluating the Safety and Toxicity of Nutraceuticals**The information in this chapter is not a formal dissemination of information by the US Food and Drug Administration and does not represent agency position or policy., Editor(s): Ramesh C. Gupta, Nutraceuticals, Academic Press, 2016, Pages 249-262, ISBN 9780128021477, https://doi.org/10.1016/B978-0-12-802147-7.00020-6.
  3. Han J, Xian Z, Zhang Y, Liu J, Liang A. Systematic Overview of Aristolochic Acids: Nephrotoxicity, Carcinogenicity, and Underlying Mechanisms. Front Pharmacol. 2019 Jun 11;10:648. doi: 10.3389/fphar.2019.00648. PMID: 31244661; PMCID: PMC6580798.
  4. Li, P. L., Huang, C. H., Mao, L., Li, J., Sheng, Z. G., & Zhu, B. Z. (2023). An unprecedented free radical mechanism for the formation of DNA adducts by the carcinogenic N-sulfonated metabolite of aristolochic acids. Free radical biology & medicine, 205, 332–345. https://doi.org/10.1016/j.freeradbiomed.2023.05.005
  5. Grollman, A. P., Shibutani, S., Moriya, M., Miller, F., Wu, L., Moll, U., Suzuki, N., Fernandes, A., Rosenquist, T., Medverec, Z., Jakovina, K., Brdar, B., Slade, N., Turesky, R. J., Goodenough, A. K., Rieger, R., Vukelić, M., & Jelaković, B. (2007). Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proceedings of the National Academy of Sciences of the United States of America, 104(29), 12129–12134. https://doi.org/10.1073/pnas.0701248104
  6. Lai MN, Wang SM, Chen PC, Chen YY, Wang JD. Population-based case-control study of Chinese herbal products containing aristolochic acid and urinary tract cancer risk. J Natl Cancer Inst. 2010 Feb 3;102(3):179-86. doi: 10.1093/jnci/djp467. Epub 2009 Dec 21. PMID: 20026811; PMCID: PMC2815723.
  7. Jhuang, JR., Chiang, CJ., Su, SY. et al. Reduction in the Incidence of Urological Cancers after the Ban on Chinese Herbal Products Containing Aristolochic Acid: An Interrupted Time-Series Analysis. Sci Rep 9, 19860 (2019). https://doi.org/10.1038/s41598-019-56394-y
  8. World Health Organization. (2005). WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems.