Aristolochic acid

Aristolochic acid I
Aristolochic acid molecule
Names
IUPAC name
8-Methoxy-6-nitrophenanthro[3,4-d][1,3]dioxole-5-carboxylic acid
Other names
Aristinic acid; Aristolochia yellow; Aristolochic acid A; Aristolochin;Aristolochine; Descresept; Tardolyt;TR 1736
Identifiers
313-67-7 Yes
ChEMBL ChEMBL93353 Yes
ChemSpider 2149 Yes
Jmol-3D images Image
KEGG C08469 Yes
PubChem 2236
Properties
Molecular formula
 C17H11NO7
Molar mass 341.27 g·mol−1
Appearance yellow powder
Melting point 260 to 265 °C (500 to 509 °F; 533 to 538 K)
Slightly soluble
Hazards
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroform Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
1
2
0
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 Yes verify (what is: Yes/?)
Infobox references

Aristolochic acids are a family of carcinogenic, mutagenic, and nephrotoxic compounds commonly found in the plant family Aristolochiaceae, including Aristolochia and Asarum (wild ginger), which are commonly used in Chinese herbal medicine.[1][2] Aristolochic acid I is the most abundant of the aristolochic acids and is found in almost all Aristolochia species.[3] Aristolochic acids are often accompanied by aristolactams.[4]

Aristolochic acids are slightly soluble in water, have a melting point between 281 and 286 degrees Celsius,[5] and have a bitter flavor.[6]

Biosynthesis

The aristolochic acids are among a group of substituted 10-nitro-1-phenantropic acids, biogenetically derived from benzylisoquinoline precursors, which in turn originate from tyrosine.[7] The biosynthesis of aristolochic acid therefore begins at tyrosine (2), which is converted to dopa (3). Dopa is subsequently converted into dopamine (4) and further converstion of dopamine into 3,4-dihydroxyphenylacetaldehyde (5) results in the formation of norlaudanosoline (6) via a spontaneous Pictet-Spengler condensation of the two molecules.[8] Evidence of these precursors was confirmed by 14C experiments where labeled compounds were administered to Aristolochia sipho and aristolochic acid was successfully extracted. Modification of norlaudanosoline is continued with a methylation of two alcohol groups to give orientaline (7). Orientaline undergoes a cyclization event to give the addition of the 5-membered ring into orientalinol (8), subsequently undergoing a methyl shift and aromatization event (9) to yield prestephanine (10).[9] The final steps are the formation of stephanine (11) and the addition of a carboxylate to yield aristolochic acid (12). Comer et al. originally proposed a postulated pathway from norlaudanosoline to aristolochic acid in 1968 very similar to the described pathway but Sharma et al. confirmed the presence of the intermediate compounds via DL-[3-14C] tyrosine trapping experiments in Aristolochia bracteata in 1982. After the general backbone of aristolochic acid is synthesized, post-synthetic modifications are performed; for example, aromatization of one of the rings yields aristolochic acid I as seen at the top of the page.

Biosynthetic pathway of Aristolochic acid

Toxicity

Aristolochic acids are hypothesized to be causative agents in Balkan endemic nephropathy;[10][11][12] and a related—possibly identical—condition known as "Chinese herbs nephropathy".[13] Exposure to aristolochic acid is associated with a high incidence of uroepithelial tumorigenesis,[14] and is linked to urothelial cancer.[15][16]

In April 2001, the Food and Drug Administration issued a consumer health alert warning against consuming botanical products, sold as "traditional medicines" or as ingredients in dietary supplements, containing aristolochic acid.[17] The agency warned that consumption of aristolochic acid-containing products was associated with "permanent kidney damage, sometimes resulting in kidney failure that has required kidney dialysis or kidney transplantation. In addition, some patients have developed certain types of cancers, most often occurring in the urinary tract."[17]

In August 2013, two studies identified an aristolochic acid mutational signature in upper urinary tract cancer patients from Taiwan.[18][19] The carcinogenic effect is the most potent found thus far, exceeding the amount of mutations in smoking-induced lung cancer and UV-exposed melanoma. Exposure to aristolochic acid may also cause certain types of liver cancer.[18]

See also

References

  1. ↑ Heinrich M, Chan J, Wanke S, Neinhuis C, Simmonds MS (August 2009). "Local uses of Aristolochia species and content of nephrotoxic aristolochic acid 1 and 2--a global assessment based on bibliographic sources". J Ethnopharmacol 125 (1): 108–44. doi:10.1016/j.jep.2009.05.028. PMID 19505558.
  2. ↑ Nolin, Thomas D. & Himmelfarb, Jonathan (2010). "Mechanisms of drug-induced nephrotoxicity". In Uetrecht, Jack. Adverse Drug Reactions. Springer. p. 123. ISBN 978-3-642-00662-3.
  3. ↑ Wu, Tian-Shung et al. (2005). "Chemical constituents and pharmacology of Aristolochia species". In Rahman, Atta-ur. Studies in Natural Products Chemistry: Bioactive Natural Products (Part L). Gulf Professional Publishing. p. 863. ISBN 978-0-444-52171-2.
  4. ↑ Wink, Michael & Schimmer, Oskar (1999). "Modes of action of defensive secondary metabolites". In Wink, Michael. Functions of plant secondary metabolites and their exploitation in biotechnology. CRC Press. p. 75. ISBN 978-0-8493-4086-4.
  5. ↑ Barceloux, Donald G. (2008). "Aristolochic acid and Chinese Herb nephropathy". Medical toxicology of natural substances: foods, fungi, medicinal herbs, plants, and venomous animals. John Wiley & Sons. p. 384. ISBN 978-0-471-72761-3.
  6. ↑ Offermanns, S. & Amara, Susan G., ed. (2006). Reviews of physiology, biochemistry and pharmacology, Volume 154. Birkhäuser. p. 56. ISBN 978-3-540-30384-8.
  7. ↑ Comer, F.; Tiwari, H.P.; Spenser, I.D. (1969), "Biosynthesis of aristolochic acid", Canadian Journal of Chemistry 47 (3): 481–487, doi:10.1139/v69-070
  8. ↑ Hoover, Larry K.; Moo-young, Murray; Legge, Raymond L. (1991), "Biotransformation of Dopamine to Norlaudanosoline by Aspergillus niger", Biotechnology and Bioengineering 38 (9): 1029–1033, doi:10.1002/bit.260380911
  9. ↑ Sharma, Vidur; Jain, Sudha; Bhakuni, Dewan S.; Kapil, Randhir S. (1982), "Biosynthesis of aristolochic acid", Journal of the Chemical Society, Perkin Transcations 1 1 (0): 1153–1155, doi:10.1039/p19820001153
  10. ↑ Gluhovschi G, Margineanu F, Velciov S, Gluhovschi C, Bob F, Petrica L, Bozdog G, Trandafirescu V, Modalca M (January 2011). "Fifty years of Balkan endemic nephropathy in Romania: some aspects of the endemic focus in the Mehedinti county". Clin. Nephrol. 75 (1): 34–48. PMID 21176749.
  11. ↑ Geacintov, Nicholas E. & Broyde, Suse, ed. (2010). "Introduction and perspectives on the Chemistry and Biology of DNA Damage". The Chemical Biology of DNA Damage. Wiley-VCH. p. 7. ISBN 978-3-527-32295-4.
  12. ↑ Wild, Chris et al., ed. (2008). Molecular epidemiology of chronic diseases. John Wiley & Sons. p. 113. ISBN 978-0-470-02743-1.
  13. ↑ De Broe ME (March 2012). "Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy". Kidney Int. 81 (6): 513–5. doi:10.1038/ki.2011.428. PMID 22373701.
  14. ↑ Ronco, Claudio et al., ed. (2008). Critical care nephrology. Elsevier Health Sciences. p. 1699. ISBN 978-1-4160-4252-5.
  15. ↑ Chen CH, Dickman KG, Moriya M, Zavadil J, Sidorenko VS, Edwards KL, Gnatenko DV, Wu L, Turesky RJ, Wu XR, Pu YS, Grollman AP (May 2012). "Aristolochic acid-associated urothelial cancer in Taiwan". Proc. Natl. Acad. Sci. U.S.A. 109 (21): 8241–6. doi:10.1073/pnas.1119920109. PMC 3361449. PMID 22493262.
  16. ↑ Lai, M.-N.; Wang, S.-M.; Chen, P.-C.; Chen, Y.-Y.; Wang, J.-D. (2009). "Population-Based Case-Control Study of Chinese Herbal Products Containing Aristolochic Acid and Urinary Tract Cancer Risk". JNCI Journal of the National Cancer Institute 102 (3): 179. doi:10.1093/jnci/djp467.
  17. ↑ 17.0 17.1 FDA Warns Consumers to Discontinue Use of Botanical Products that Contain Aristolochic acid. April 11, 2001.
  18. ↑ 18.0 18.1 Poon, S. L.; Pang, S.-T.; McPherson, J. R.; Yu, W.; Huang, K. K.; Guan, P.; Weng, W.-H.; Siew, E. Y.; Liu, Y. (2013). "Genome-Wide Mutational Signatures of Aristolochic Acid and Its Application as a Screening Tool". Science Translational Medicine 5 (197): 197ra101. doi:10.1126/scitranslmed.3006086. PMID 23926199.
  19. ↑ Hoang, M. L.; Chen, C.-H.; Sidorenko, V. S.; He, J.; Dickman, K. G.; Yun, B. H.; Moriya, M.; Niknafs, N.; Douville, C. (2013). "Mutational Signature of Aristolochic Acid Exposure as Revealed by Whole-Exome Sequencing". Science Translational Medicine 5 (197): 197ra102. doi:10.1126/scitranslmed.3006200. PMID 23926200.

Further reading

External links

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