The Natural Product Aristolochic Acid - Essay Example

A Report on the natural product Aristolochic acid Aristolochic acid is made of a mixture of both aristolochic acid I and aristolochic acid II in a 1:1 ratio. Aristolochic acid is highly carcinogenic (cancer-causing) and nephrotoxic (harms the nephrons in the kidneys) [1]. Normally, this type of acid is found in several natural, botanical products sold commonly as 'traditional medicines' and in diet-supplements/weight loss preparations [11]. Urinary tract damage and other cancers have been linked to the intake of aristolochic acid as well as kidney damage and kidney failure which requires dialysis or worse, kidney transplantation [2]. Therefore, this makes aristolochic acid both nephrotoxic and carcinogenic [11]. Aristolochic acid Chemical name Aristolochic acid Other names Aristolochic acid I Aristinic acid Aristolochia yellow Aristolochic acid A Aristolochin Aristolochine Descresept Isoaristolochic acid Tardolyt TR 1736 Aristolochic acid II Aristolochic acid B Marketing names Chemical formula C17H11NO7 Molecular mass 341.27684 g/mol CAS number 313-67-7 Density x.xxx g/cm3 Melting point 260 - 265 C Boiling point xx.x C SMILES xxx Aristolochic acid (AA) is a known genotoxic mutagen and is generally derived from plant extracts and is formed from aristolochic acid I (AAI) and aristolochic acid II (AAII), [20, 22, 17, 25] it is potentially carcinogenic to most rodent species [12, 13, 5, 25] and in humans [6, 15, 25]. The formation of DNA adducts by Aristolochic acid (AA) gives it it's mutagenic and carcinogenic properties, due to the process of reductive metabolic activation where both types of AA's (AA I and AA II) react with the nucleic acids adenine and guanine [18, 19, 25]. Structure of aristolochic acid I (R = OCH3) and aristolochic acid II (R = H). Compound Summary of Aristolochic Acid [10] Properties Computed from Structure: Molecular Weight: 341.272 g/mol Molecular Formula: C17H11NO7 XLogP: 3.519 Hydrogen Bond Donor Count: 1 Hydrogen Bond Acceptor Count: 7 Rotatable Bond Count: 2 Descriptors Computed from Structure: Canonical SMILES: COC1=CC=CC2=C3C(=C(C=C21)[N+](=O)[O-])C(=CC4=C3OCO4)C(=O)O InChI: InChI=1/C17H11NO7/c1-23-12-4-2-3-8-9(12)5-11(18(21)22)14-10(17(19)20)6-13-16(15(8)14)25-7-24-13/h2-6H,7H2,1H3,(H,19,20)/f/h19H 'Aristolochic acid is a rodent carcinogen found in the Aristolochia and Asarum species, both in the Aristolochiaceae family of plants such as the Aristolochia fangchi' [1]. Botanicals Known or Suspected to Contain Aristolochic Acid [4] Botanical Name* Common or Other Names Aristolochia spp. Aristolochia Guan mu tong Guang mu tong Aristolochia acuminata Lam. Syn. Aristolochia tagala Champ. Oval leaf Dutchman's pipe Aristolochia argentina Griseb. Aristolochia baetica Linn. Syn. Aristolochia bracteolata Lam. Aristolochia bracteata Retz. Ukulwe Aristolochia chilensis Bridges in Lindl. Aristolochia cinnabarina C.Y. Cheng & J.L. Wu Aristolochia clematitis L. Birthwort Aristolochia contorta Bunge Ma dou ling Tian xian teng Aristolochia cymbifera Mart. & Zucc. Mil homens Aristolochia debilis Siebold & Zucc. Syn. Aristolochia longa Thunb. Syn. Aristolochia recurvilabra Hance Syn. Aristolochia sinarum Lindl. Ma dou ling Tian xian teng Qing mu xiang Sei-mokkou (Japanese) Birthwort Long birthwort Aristolochia elegans Mast. Syn. Aristolochia hassleriana Chodat Aristolochia esperanzae Kuntze Aristolochia fangchi Y.C. Wu ex L.D. Chow & S.M. Hwang Guang fang ji Fang ji Mokuboi (Japanese) Kwangbanggi (Korean) Fang chi Kou-boui (Japanese) Aristolochia fimbriata Cham. Aristolochia indica L. Indian birthwort Aristolochia kaempferi Willd. Syn. Aristolochia chrysops (Stapf) E.H. Wilson ex Rehder Syn. Aristolochia feddei H. Lv. Syn. Aristolochia heterophylla Hemsl. Syn. Aristolochia mollis Dunn Syn. Aristolochia setchuenensis Franch. Syn. Aristolochia shimadai Hayata Syn. Aristolochia thibetica Franch. Syn. Isotrema chrysops Stapf Syn. Isotrema heterophylla (Hemsl.) Stapf Syn. Isotrema lasiops Stapf Yellowmouth Dutchman's pipe Aristolochia kwangsiensis Chun & F.C. How Syn. Aristolochia austroszechuanica C. B. Chien & C. Y. Cheng Aristolochia macrophylla Lam. Syn. Aristolochia sipho L'Hr. Dutchman's-pipe Aristolochia manschuriensis Kom. Syn. Hocquartia manshuriensis (Kom.) Nakai Syn. Isotrema manchuriensis (Kom.) H. Huber Manchurian birthwort Manchurian Dutchman's pipe Guang mu tong Kan-Mokutsu (Japanese) Mokuboi (Japanese) Kwangbanggi (Korean) Aristolochia maurorum L. Aristolochia maxima Jacq. Syn. Aristolochia maxima var. angustifolia Duchartre in DC. Syn. Howardia hoffmannii Klotzsch Aristolochia mollissima Hance Aristolochia pistolochia L. Aristolochia rigida Duch. Aristolochia rotunda Linn. Aristolochia serpentaria L. Syn. Aristolochia serpentaria var. hastata (Nutt.) Duch. Virginia snakeroot Serpentaria Virginia serpentary Aristolochia watsoni Wooton & Standley or Aristolochia watsonii Wooton & Standley Syn. Aristolochia porphyrophylla Pfeifer Aristolochia westlandii Hemsl. or Aristolochia westlandi Hemsl. Aristolochia zollingeriana Miq. Syn. Aristolochia kankauensis Sasaki Syn. Aristolochia roxburghiana subsp. kankauensis (Sasaki) Kitam. Syn. Hocquartia kankauensis (Sasaki) Nakai ex Masam. Syn. Aristolochia tagala var. kankauensis (Sasaki) T. Yamaz. Asarum canadense Linn. Syn. Asarum acuminatum (Ashe) E.P. Bicknell Syn. Asarum ambiguum (E.P. Bicknell) Daniels Syn. Asarum canadense var. ambiguum (E.P. Bicknell) Farw. Syn. Asarum canadense var. reflexum (E.P. Bicknell) B.L. Rob. Syn. Asarum furcatum Raf. Syn. Asarum medium Raf. Syn. Asarum parvifolium Raf. Syn. Asarum reflexum E.P. Bicknell Syn. Asarum rubrocinctum Peattie Wild ginger Indian ginger Canada snakeroot False coltsfoot Colic root Heart snakeroot Vermont snakeroot Southern snakeroot Asarum himalaicum Hook. f. & Thomson ex Klotzsch or Asarum himalaycum Hook. f. & Thomson ex Klotzsch Tanyou-saishin (Japanese) Asarum splendens (F. Maek.) C.Y. Cheng & C.S. Yang Do-saishin (Japanese) Bragantia wallichii R.Br. Specimen exists at New York Botanical Gardens. Tropicos does not list this species as a synonym for any Thottea species. Kew Gardens Herbarium does not recognize the genera Bragantia. Until additional information is obtained we will use the name as cited in J. Nat. Products 45:657-666 (1982) Source: Center for Food Safety and Applied Nutrition. (2001c) Using a laboratory-made pressurized liquid extraction (PLE) method set at the dynamic mode, Aristolochic acids I and II can be extracted from medicinal plants. If the intended extracts will be extracted from medicinal plants, spiking (addition of enzymes or other catalytic substances) will not be done, but ultrasonic and Sohxlet extraction will both be done to determine the accuracy of the techniques. Temperature, volume of solvent and particle size is also evaluated during the extraction process. A method precision (n=5) rate of 1.98 - 3.4% is attained for Aristolochic acids I and II extraction in medicinal plants but can be up to 8% for lower levels of aristolochic acid II in medicinal plants [16]. A recent study in the U.S. has shown that '1H NMR methodology for the simultaneous determination and characterization of the nephrotoxic components of Aristolochia plants aristolochic acid I (AA-I) and aristolochic acid II (AA-II) was developed utilizing a 400-MHz spectrometer without the need of reference standards. The developed methodology is able to differentiate and assess chemical structures of these toxic injurious compounds'. In another study published in Pharmazie (NMR regulatory analysis: determination and characterization of Chinese-herb aristolochic acids), George M. Hanna from the U.S. Food and Drug Administration reports that 'The quantity of each was calculated on the basis of the integrals for the signals of the H-7 and H-8 of the phenanthrene ring of AA-I and AA-II at delta7.38 and delta8.31, respectively, and the vinylic protons of the internal standard maleic acid at delta6.06,'. He continued stating that 'The accuracy of the method was established through the analysis of synthetic mixtures containing the internal standard maleic acid, with purified AA-I or combined AA-I and AA-II sodium salts. Excellent agreements were verified between the assay results and the quantities in the mixtures.' He also stated that : 'The meanplusmnSD recovery values for purified AA-I and combined AA-I and AA-II from two sets of 10 synthetic mixtures were 99.8plusmn0.6% and 99.6plusmn0.8%, respectively,' Hanna also states that: 'The assay of four lots of commercial aristolochic acid by 1H NMR spectroscopy indicated AA-I and AA-II contents in the ranges 45.3-97.1% and 0-15.4%, respectively' [7]. Aristolochic acid theoretically has anti-viral, carcinogenic and mutagenic properties. Recently, the FDA issued an alert on the import any plant agent labelled with or containing traces of Aristolochia plant to avoid cofusion [4]. Approximately 100 cases of renal disease patients in Belgium has been reported to have undergone a 'slimming regimen' from 1990-92, which included the consumption of a certain weight-reducing pill containing unknown powdered herbs. Lesions in their kidneys were made of extensive renal interstitial fibrosis with atrophy and loss of tubules. 70% of the patients were administered dialysis while some were required to undergo kidney transplants. Findings in this case concluded that Stephania tetrandra was replaced with Aristolochia fangchi, a herb which contains aristolochic acid. This mix up happened because their Chinese names translations were similar [4]. Another similar outbreak occurred again in Belgium, involving another 100 patients, mostly middle-aged women also undergoing slimming regimens. Another mix-up of Aristolochia fangchi and Stephania tetrandra has occurred but rapid progressive renal fibrosis resulted from the patients this time. Additional occurrences of rapid progressive renal fibrosis through the intake of Chinese herbs have been reported in other parts of Europe and also in Asia. This resulted for the syndrome to be called 'Chinese herb nephropathy' [8]. There are also a few early reported cases of uorthelial cancer in Belgium, apparently due to 'Chinese herb nephropathy.' These individuals have 'end-stage renal disease and were offered prophylactic nephroureterectomy.' Prophylactic nephroureterectomy is a surgical procedure that leads to the detection of pre-invasive and invasive neoplastic lesions of the renal pelvis, the ureter and the urinary bladder in patients diagnosed with Chinese herb nephropathy. 18 out of 39 renal cancer patients had more than the number of expected tumours in them. A positive direct proportion between the intake of Chinese herbal medicines and the occurrence of tumours. Clinically invasive cancer has been detected in Chinese herb nephropathy patients who are not undergoing prophylactic nephroureterectomy [8]. The detection and identification of aristolochic acids in herbal mixtures consumed by patients are done using phytochemical investigation techniques [8]. 'In 1996, it was reported that aristolochic acid-related DNA adducts had been detected in renal tissue from 5 of the original Belgian patients'. Although there is a batch by batch differences in the chemical composition of Chinese herbal mixtures consumed in Belgian slimming clinics. All patients were found to have specific aristolochic acid-DNA adducts in their urothelial tissue specimens. This provided evidence that consumption of products from Aristolochia is carcinogeic [23, 3]. 2 new cases of interstitial fibrosis were detected in the UK last August 1999, where patients who were believed to have taken a certain amounts of 'botanical preparations containing aristolochic acid'. One of the patients has already been undergone kidney transplant whilst the other waited for a little while for a kidney transplant though both developed end-stage renal failure [10, 3]. Aristolochic acid is an alkaloid which has been found out to have anti-inflammatory activities in mouse foot pad edemas resulting from the introduction of phospholipases A2 from synovial fluid of humans. Present investigations on the effects of aristolochic acid on phospholipase activation and arachidonic acid movement in human neutrophils yielded satisfactory results such as the fact that aristolochic acid is a dose-dependent inhibitor of the calcium-dependent neutral active known as phospholipase A2 which were extracted from human neutrophils. 'A23187-stimulated release' of formerly integrated '[3H] arachidonate from whole neutrophils is subdued by aristolochic acid by as much as 90%', this effect depends on the dose. In 5 minutes, the effect of 'aristolochic acid' with an 'IC50 of 40 microM' rapidly proceeds with close optimum inhibition. 'A23187-motivated loss of [3H] arachidonate' from both choline- and inositol-phospholipids is stopped by aristolochic acid. Lowered dose released of 'free [3H]arachidonate' is escorted by a associated reduction in the production of '[3H]leukotriene B4 and [3H]hydroxyeicosatetraenoic acids'. Aristolochic acid also stops the 'A23187-stimulated production of [3H] alkylacetylglycerophosphocholine' from '[3H] alkylacylglycerophosphocholine in cells'. 'A23187-stimulated phospholipase A2' activity in human neutrophils being inhibited by aristolochic acid shows that it is a significant 'inhibitor' of these substances [21]. Aristolochia contorta, Aristolochia. debilis, Aristolochia. fangchi and Aristolochia manshuriensis and other Aristolochia species have been utilised in traditional Chinese medicine as a treatment for 'rheumatics, as a diuretic and in the treatment of oedema'. Aristolochia species have Aristolochic acids (nitrophenanthrene carboxylic acid derivatives) in them [8]. Some herbal products containing aristolochic acid: Product Name Responsible Firm Rheumixx PharmaBotanixx, Irvine, CA (Distributor), Sun Ten Laboratories, Inc., Irvine, CA (Manufacturer) BioSlim Doctor's Natural Weight Loss System Slim Tone Formula Thane International, LaQuinta, CA (Distributor) Prostatin Herbal Doctor Remedies, Monterey Park, CA (Distributor) Fang Ji Stephania Lotus Herbs Inc., LaPuente, CA (Distributor) Mu Tong Clematis armandi Lotus Herbs Inc., LaPuente, CA (Distributor) Meridian Circulation East Earth Herb Inc. (Brand name Jade Pharmacy), Eugene, OR Temple of Heaven Chinese Herbs Radix aristolochiae Mayway Corporation, Oakland, CA (Distributor) and Almira Alchemy, Alachua, FL (Distributor) Qualiherb Chinese Herbal Formulas Dianthus Formulas Ba Zheng San QualiHerb (Division of Finemost), Cerritos, CA (Distributor) Clematis & Carthamus Formula 21280 (2 samples) QualiHerb (Division of Finemost), Cerritos, CA (Distributor) Virginia Snake Root, Cut Aristolochia serpentaria (2 samples) Penn Herb Co., Philadelphia, PA (Manufacturer) Green Kingdom Akebia Extract Green Kingdom Herbs, Bay City, MI (Manufacturer) Ava Health, Grove City, OH (Distributor) Green Kingdom Stephania Extract Green Kingdom Herbs, Bay City, MI Ava Health (Distributor) Neo Concept Aller Relief BMK International, Inc., Wellesley, MA (Distributor), Sun Ten Labs, Irvine, CA (Manufacturer) Mu Tong Clematis armandi Botanicum.com, Winnipeg, Canada and Pembina, ND Fang Ji Stephania Botanicum.com, Winnipeg, Canada and Pembina, ND Stephania tetrandra, roots, whole (1) Product labeling states "Not for human consumption." Ethnobotanical, Racine, WI Joint Ease/Joint Comfort Complex not available Source: http://www.cfsan.fda.gov Reference List 1. "Aristolochic acid." (2005). Wikipedia. Wikimedia Foundation, Inc. Available from: http://en.wikipedia.org/wiki/Aristolochic_acid [Accessed 22 March 2006]. 2. Center for Food Safety and Applied Nutrition. (2001a). FDA WARNS CONSUMERS TO DISCONTINUE USE OF BOTANICAL PRODUCTS THAT CONTAINARISTOLOCHIC ACID. U.S. Food and Drug Administration. Available from: http://www.cfsan.fda.gov/%20dms/addsbot.html [Accessed 22 March 2006]. 3. Center for Food Safety and Applied Nutrition. (2001b). Letter to Health Professionals Regarding Safety Concerns Related to the Use of Botanical Products Containing Aristolochic Acid. U. S. Food and Drug Administration. Office of Nutritional Products, Labeling, and Dietary Supplements. Available from: http://www.cfsan.fda.gov/dms/ds-botl3.html [Accessed 22, 2006]. 4. Center for Food Safety and Applied Nutrition. (2001c). Listing of Botanical Ingredients of Concern. Office of Nutritional Products, Labeling, and Dietary Supplements. U. S. Food and Drug AdministrationAvailable from: http://www.cfsan.fda.gov/dms/ds-bot2.html [Accessed 22 March 2006]. 5. Cosyns,J.-P., Goebbels,R.-M., Liberton,V., Schmeiser,H.H., Bieler,C.A. and Bernard,A.M. (1998) Chinese herbs nephropathy-associated slimming regimen induces tumors in the forestomach but no interstitial nephropathy in rats. Arch. Toxicol., 72, 738-743. 6. Cosyns,J.-P., Jadoul,M., Squifflet,J.P., Wese,F.X. and van Ypersele de Strihou,C. (1999) Urothelial lesions in Chinese-herb nephropathy. Am. J. Kidney Dis., 33, 1011-1017. 7. Florida College of Integrative medicine. (n.d.). Complementary and Alternative Medicine. Florida College of Integrative medicine. Available from: http://fcim.edu/story.cfmloc=63 [Accessed 22 March 2006]. 8. International Agency for Research on Cancer (IARC). (2002). ARISTOLOCHIA SPECIES AND ARISTOLOCHIC ACIDS, VOL.: 82 (2002) (p. 69), Available from: http://www.inchem.org/documents/iarc/vol82/82-01.html [Accessed 22 March 2006]. 9. Krumbiegel G, Hallensleben J, Mennicke WH, Rittmann N, Roth HJ.(1987). Studies on the metabolism of aristolochic acids I and II. Xenobiotica. 1987 Aug;17(8):981-91. 10. Lord GM et al. Nephropathy caused by Chinese herbs in the UK. Lancet 1999;354:481-2 11. MedicineNet. (2003). Definition of Aristolochic acid. MedicineNet, Inc. Available from: http://www.medterms.com/script/main/art.asparticlekey=24794 [Accessed 22 March 2006]. 12. Mengs,U., Lang,W. and Poch,J.A. (1982) The carcinogenic action of aristolochic acid in rats. Arch. Toxicol., 51, 107-119. 13. Mengs,U. (1988) Tumor induction in mice following exposure to aristolochic acid. Arch. Toxicol., 61, 504-505. 14. National Center for Biotechnology Information. (2006). Compound Summary: U.S. National Library of Medicine. Available from: http://pubchem.ncbi. nlm.nih.gov/summary/summary.cgicid=2236 [Accessed 22 March 2006]. 15. Nortier,J.L., Muniz,M.-C., Schmeiser,H.H. et al. (2000) Urothelial carcinoma associated with the use of Chinese herbs (Aristolochia species). New Engl. J. Med., 342, 1686-1692. 16. Ong ES, Woo SO, Yong YL.(n.d.). Pressurized liquid extraction of berberine and aristolochic acids in medicinal plants.Department of Scientific Services, Institute of Science and Forensic Medicine, Singapore. 17. Pezutto,J.M., Swanson,S.M., Woongchon,M., Che,C., Cordell,G.A. and Fong,H.H.S. (1988) Evaluation of the mutagenic and cytostatic potential of aristolochic acid (3,4-methylenedioxy-8-methoxy-10-nitrophenanthrene-1-carboxylic acid) and several of its derivatives. Mutat. Res., 206, 447-454. 18. Pfau,W., Schmeiser,H.H. and Wiessler,M. (1990) Aristolochic acid binds covalently to the exocyclic amino group of purine nucleotides in DNA. Carcinogenesis, 11, 313-319. 19. Pfau,W., Schmeiser,H.H. and Wiessler,M. (1991) N6-Adenyl arylation of DNA by aristolochic acid II and a synthetic model for the putative proximate carcinogen. Chem. Res. Toxicol., 4, 581-586. 20.Robisch,G., Schimmer,O. and Gggelmann,W. (1982) Aristolochic acid is a direct mutagen in Salmonella typhimurium. Mutat. Res., 105, 201-204. 21. Rosenthal MD, Vishwanath BS, Franson RC.(1989). Effects of aristolochic acid on phospholipase A2 activity and arachidonate metabolism of human neutrophils. Biochim Biophys Acta. 1989 Jan 23;1001(1):1-8. 22. Schmeiser,H.H., Pool,B.L. and Wiessler,M. (1986) Identification and mutagenicity of metabolites of aristolochic acid formed by rat liver. Carcinogenesis, 7, 59-63. 23. Schmeiser HH et al. (1996). Detection of DNA adducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy. Cancer Res 1996;56:2025-8 24. Shiel, William, md. (2004).Herb Danger - Aristolochic Acid Warning. MedicineNet, Inc. Available from: http://www.medicinenet.com/script/main/art.asparticlekey=17499 [Accessed 22 March 2006]. 25. Volker M. Arlt, Heinz H. Schmeiser2 and Gerd P. Pfeifer. (2001). Sequence-specific detection of aristolochic acid-DNA adducts in the human p53 gene by terminal transferase-dependent PCR. Carcinogenesis, Vol. 22, No. 1, 133-140, Oxford University Press. Read More