aristolochic acids

Summary

Summary: Nitro-phenanthrenes occurring in ARISTOLOCHIACEAE and other plants. They derive from stephanine (APORPHINES) by oxidative ring cleavage. The nitro group is a reactive alkylator (ALKYLATING AGENTS) that binds to biological macromolecules. Ingestion by humans is associated with nephropathy (NEPHRITIS). There is no relationship to the similar named aristolochene (SESQUITERPENES).

Top Publications

  1. Arlt V, Zuo J, Trenz K, Roufosse C, Lord G, Nortier J, et al. Gene expression changes induced by the human carcinogen aristolochic acid I in renal and hepatic tissue of mice. Int J Cancer. 2011;128:21-32 pubmed publisher
    ..Several genes identified such as TP53, Rb1, Mdm2, Cdkn2a and Myc are frequently affected in human urothelial cancer, and may be valuable prognostic markers in future clinical studies. ..
  2. Pfohl Leszkowicz A. Ochratoxin A and aristolochic acid involvement in nephropathies and associated urothelial tract tumours. Arh Hig Rada Toksikol. 2009;60:465-83 pubmed publisher
    ..Recent theories however have implicated aristolochic acids (AA)...
  3. Liu M, Lin T, Wu T, Yu F, Lu C, Liu B. Aristolochic acid I suppressed iNOS gene expression and NF-?B activation in stimulated macrophage cells. Toxicol Lett. 2011;202:93-9 pubmed publisher
    ..The stability of iNOS mRNA was not the target of AAI inhibition. ..
  4. Peraica M, Domijan A, Saric M. Mycotoxic and aristolochic acid theories of the development of endemic nephropathy. Arh Hig Rada Toksikol. 2008;59:59-65 pubmed publisher
    ..This paper presents most important studies supporting both theories, indicating also the inconsistencies of each...
  5. Debelle F, Nortier J, Husson C, De Prez E, Vienne A, Rombaut K, et al. The renin-angiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids. Kidney Int. 2004;66:1815-25 pubmed
    ..interstitial fibrosis, tubular atrophy, and chronic renal failure, was reported after 35-day injections of aristolochic acids (AA) to salt-depleted male Wistar rats...
  6. Pozdzik A, Salmon I, Debelle F, Decaestecker C, Van den Branden C, Verbeelen D, et al. Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation. Kidney Int. 2008;73:595-607 pubmed
    ..We suggest that resident fibroblast activation plays a critical role in the process of renal fibrosis during aristolochic acid toxicity. ..
  7. Kucab J, Phillips D, Arlt V. Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock-in (Hupki) mouse model. FEBS J. 2010;277:2567-83 pubmed publisher
    ..Despite the utility of the current Hupki embryo fibroblast immortalization assay, it has several limitations that could be addressed by future developments, in order to improve its sensitivity and selectivity. ..
  8. Arlt V, Stiborova M, Schmeiser H. Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis. 2002;17:265-77 pubmed
    ..Therefore, all products containing botanicals known to or suspected of containing AA should be banned from the market world wide. ..
  9. Pfohl Leszkowicz A, Tozlovanu M, Manderville R, Peraica M, Castegnaro M, Stefanovic V. New molecular and field evidences for the implication of mycotoxins but not aristolochic acid in human nephropathy and urinary tract tumor. Mol Nutr Food Res. 2007;51:1131-46 pubmed
    To find out whether ochratoxin A (OTA), citrinin (CIT), aristolochic acids (AA) are etiologic agents of Balkan endemic nephropathy (BEN) or Chinese herbal nephrotoxicity, and associated urinary tract tumor (UTT), we have compared (i) in ..

More Information

Publications62

  1. Moriya M, Slade N, Brdar B, Medverec Z, Tomic K, Jelakovic B, et al. TP53 Mutational signature for aristolochic acid: an environmental carcinogen. Int J Cancer. 2011;129:1532-6 pubmed publisher
  2. Mei N, Arlt V, Phillips D, Heflich R, Chen T. DNA adduct formation and mutation induction by aristolochic acid in rat kidney and liver. Mutat Res. 2006;602:83-91 pubmed
    ..Although the same treatment does not produce tumors in rat liver, it does induce DNA adducts and mutations in this tissue, albeit at lower levels than in kidney. ..
  3. Liu M, Maruyama S, Mizuno M, Morita Y, Hanaki S, Yuzawa Y, et al. The nephrotoxicity of Aristolochia manshuriensis in rats is attributable to its aristolochic acids. Clin Exp Nephrol. 2003;7:186-94 pubmed
    ..recently shown to be nephrotoxic in rats, less is known about whether this toxicity is attributable to its aristolochic acids (AA)...
  4. Das A, Bhadra K, Achari B, Chakraborty P, Kumar G. Interaction of aristololactam-?-D-glucoside and daunomycin with poly(A): spectroscopic and calorimetric studies. Biophys Chem. 2011;155:10-9 pubmed publisher
    ..No self-structure formation was observed in poly(A) with both daunomycin and aristololactam-?-D-glucoside suggesting the hindrance of the sugar moiety for such structural organization. ..
  5. Fu X, Liu Y, Li W, Pang N, Nie H, Liu H, et al. Analysis of aristolochic acids by CE-MS with carboxymethyl chitosan-coated capillary. Electrophoresis. 2009;30:1783-9 pubmed publisher
    ..As an application example, a spiked sample in human serum was analyzed by the CE-MS method, indicating that the new CE-MS method can be applied to analyze AAs in biological samples. ..
  6. Cheung T, Xue C, Leung K, Chan K, Li C. Aristolochic acids detected in some raw Chinese medicinal herbs and manufactured herbal products--a consequence of inappropriate nomenclature and imprecise labelling?. Clin Toxicol (Phila). 2006;44:371-8 pubmed
    ..These were purchased in 2001, before the prohibition. The contents of aristolochic acids of each was determined by high pressure liquid chromatography (HPLC), and confirmed by liquid chromatography-..
  7. Cheng C, Chen K, Shih P, Lu L, Hung C, Lin W, et al. Chronic renal failure rats are highly sensitive to aristolochic acids, which are nephrotoxic and carcinogenic agents. Cancer Lett. 2006;232:236-42 pubmed
    ..In addition, no such mutations were found in the tissues of CRF rats without AA treatment or healthy rats fed with AA. Our results strongly demonstrated that AA was in fact nephrotoxic and carcinogenic, especially to those CRF rats. ..
  8. de Jonge H, Vanrenterghem Y. Aristolochic acid: the common culprit of Chinese herbs nephropathy and Balkan endemic nephropathy. Nephrol Dial Transplant. 2008;23:39-41 pubmed
  9. Stiborova M, Frei E, Wiessler M, Schmeiser H. Human enzymes involved in the metabolic activation of carcinogenic aristolochic acids: evidence for reductive activation by cytochromes P450 1A1 and 1A2. Chem Res Toxicol. 2001;14:1128-37 pubmed
    ..These results are the first report on the activation of AA by human enzymes and clearly demonstrate the role of P450 1A1, 1A2, and NADPH:P450 reductase in catalyzing the reductive activation of AA. ..
  10. Kumar V, Poonam -, Prasad A, Parmar V. Naturally occurring aristolactams, aristolochic acids and dioxoaporphines and their biological activities. Nat Prod Rep. 2003;20:565-83 pubmed
    ..chromophore are a small group of compounds mainly found in the Aristolochiaceae together with the aristolochic acids and 4,5-dioxoaporphines...
  11. Stiborova M, Frei E, Hodek P, Wiessler M, Schmeiser H. Human hepatic and renal microsomes, cytochromes P450 1A1/2, NADPH:cytochrome P450 reductase and prostaglandin H synthase mediate the formation of aristolochic acid-DNA adducts found in patients with urothelial cancer. Int J Cancer. 2005;113:189-97 pubmed
    ..In addition, prostaglandin H synthase is another enzyme activating AAI in renal microsomes. The results demonstrate for the first time the potential of microsomal enzymes in human liver and kidney to activate AAI by nitroreduction. ..
  12. Qi X, Cai Y, Gong L, Liu L, Chen F, Xiao Y, et al. Role of mitochondrial permeability transition in human renal tubular epithelial cell death induced by aristolochic acid. Toxicol Appl Pharmacol. 2007;222:105-10 pubmed
    ..Taken together, these results suggested that MPT plays a critical role in the pathogenesis of HK-2 cell injury induced by AAI and implied that MPT might contribute to human nephrotoxicity of aristolochic acid. ..
  13. Simões M, Hockley S, Schwerdtle T, Gamboa da Costa G, Schmeiser H, Phillips D, et al. Gene expression profiles modulated by the human carcinogen aristolochic acid I in human cancer cells and their dependence on TP53. Toxicol Appl Pharmacol. 2008;232:86-98 pubmed publisher
    ..These results strengthen the importance of TP53 in AA-induced cancer, and indicate that other alterations, e.g. to MYC oncogenic pathways, may also contribute. ..
  14. Jacob S, Smith N, Legido Quigley C. Assessment of Chinese medicinal herb metabolite profiles by UPLC-MS-based methodology for the detection of aristolochic acids. J Sep Sci. 2007;30:1200-6 pubmed
    ..All the samples were analysed by multiple reaction monitoring (MRM) to check for the presence of aristolochic acids I and II...
  15. Yang H, Wang J, Lo T, Chen P. Occupational exposure to herbs containing aristolochic acids increases the risk of urothelial carcinoma in Chinese herbalists. J Urol. 2013;189:48-52 pubmed publisher
    Aristolochic acid can cause urothelial carcinoma. Herbal remedies containing aristolochic acids were previously categorized as proven group 1 human carcinogens by the WHO cancer agency, the International Agency for Research on Cancer...
  16. Sistkova J, Hudecek J, Hodek P, Frei E, Schmeiser H, Stiborova M. Human cytochromes P450 1A1 and 1A2 participate in detoxication of carcinogenic aristolochic acid. Neuro Endocrinol Lett. 2008;29:733-7 pubmed
    ..The aim of the study was to resolve which cytochromes P450 (CYP) detoxicate the major component of AA, aristolochic acid I (AAI), to its O-demethylated metabolite, aristolochic acid Ia (AAIa)...
  17. Kohara A, Suzuki T, Honma M, Ohwada T, Hayashi M. Mutagenicity of aristolochic acid in the lambda/lacZ transgenic mouse (MutaMouse). Mutat Res. 2002;515:63-72 pubmed
    ..These results suggested that AA, which is activated by cytochrome P450 and peroxidase to form cyclic nitrenium ions that bind to deoxyadenine, caused the A to T transversions in the target organs of mice. ..
  18. Ong E, Woo S. Determination of aristolochic acids in medicinal plants (Chinese) prepared medicine using capillary zone electrophoresis. Electrophoresis. 2001;22:2236-41 pubmed
    b>Aristolochic acids (I and II) are commonly found in medicinal plants such as Radix aristolochiae and have been reported to cause acute hepatitis and end-stage renal failure...
  19. Chen M, Su M, Zhao L, Jiang J, Liu P, Cheng J, et al. Metabonomic study of aristolochic acid-induced nephrotoxicity in rats. J Proteome Res. 2006;5:995-1002 pubmed
  20. Attaluri S, Bonala R, Yang I, Lukin M, Wen Y, Grollman A, et al. DNA adducts of aristolochic acid II: total synthesis and site-specific mutagenesis studies in mammalian cells. Nucleic Acids Res. 2010;38:339-52 pubmed publisher
    b>Aristolochic acids I and II (AA-I, AA-II) are found in all Aristolochia species...
  21. Couture A, Deniau E, Grandclaudon P, Rybalko Rosen H, Leonce S, Pfeiffer B, et al. Synthesis and biological evaluation of aristolactams. Bioorg Med Chem Lett. 2002;12:3557-9 pubmed
    ..Modulations were carried out on the phenanthrene nucleus and the lactam moiety as well. N-(N-dialkylaminoalkyl) derivatives exhibited interesting cytotoxic activity against the L1210 leukemia cell line...
  22. Stiborova M, Frei E, Arlt V, Schmeiser H. Metabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy. Mutat Res. 2008;658:55-67 pubmed
  23. Nortier J, Vanherweghem J. For patients taking herbal therapy--lessons from aristolochic acid nephropathy. Nephrol Dial Transplant. 2007;22:1512-7 pubmed
  24. Cao J, Yang X, Wang X, Qu L, Liu G, Li X. [Differential changes of intrarenal oxygenation in rat models of acute tubular necrosis caused by aristolochic acid and gentamicin]. Zhonghua Yi Xue Za Zhi. 2010;90:1208-12 pubmed
    To investigate the characteristics of renal oxygenation status in aristolochic acids I (AA-I) induced ATN rat model by method of blood oxygenation level-dependent MRI (BOLD-MRI) and compare it with ATN model caused by gentamicin...
  25. Ong E, Woo S, Yong Y. Pressurized liquid extraction of berberine and aristolochic acids in medicinal plants. J Chromatogr A. 2000;904:57-64 pubmed
    Berberine and aristolochic acids I and II present naturally in medicinal plants were extracted using a laboratory-made pressurized liquid extraction (PLE) system in the dynamic mode...
  26. Cosyns J, Dehoux J, Guiot Y, Goebbels R, Robert A, Bernard A, et al. Chronic aristolochic acid toxicity in rabbits: a model of Chinese herbs nephropathy?. Kidney Int. 2001;59:2164-73 pubmed
    ..Our observations therefore support a causal role of AA alone in the genesis of this new nephropathy. ..
  27. Hsin Y, Cheng C, Tzen J, Wu M, Shu K, Chen H. Effect of aristolochic acid on intracellular calcium concentration and its links with apoptosis in renal tubular cells. Apoptosis. 2006;11:2167-77 pubmed
    ..In conclusion, our results demonstrate an impact of AA to intracellular Ca(2+) concentration and its link with AA-induced cytotoxicity. ..
  28. Koh H, Wang H, Zhou S, Chan E, Woo S. Detection of aristolochic acid I, tetrandrine and fangchinoline in medicinal plants by high performance liquid chromatography and liquid chromatography/mass spectrometry. J Pharm Biomed Anal. 2006;40:653-61 pubmed
    ..tetrandra by A. fangchi at wholesale or retail level. This study highlights the importance of greater control of medicinal plants with toxic components as these may still be readily accessible to the public...
  29. Shibutani S, Dong H, Suzuki N, Ueda S, Miller F, Grollman A. Selective toxicity of aristolochic acids I and II. Drug Metab Dispos. 2007;35:1217-22 pubmed
    Ingestion of herbal remedies containing aristolochic acids (AAs) is associated with the development of a syndrome, designated aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial ..
  30. Yang S, Chu P, Lin Y, Chen A, Lin S. Aristolochic acid-induced Fanconi's syndrome and nephropathy presenting as hypokalemic paralysis. Am J Kidney Dis. 2002;39:E14 pubmed
    ..A renal biopsy specimen revealed typical findings of aristolochic acid-associated nephropathy. Aristolochic acids were detected in the consumed Chinese herbs...
  31. Li J, Zhang L, Jiang Z, Shu B, Li F, Bao Q, et al. Toxicities of aristolochic acid I and aristololactam I in cultured renal epithelial cells. Toxicol In Vitro. 2010;24:1092-7 pubmed publisher
    ..These results also suggested that the cytotoxic potency of AL-I is higher than that of AA-I and that the cytotoxic effects of these molecules are mediated through the induction of apoptosis in a caspase 3-dependent pathway. ..
  32. Isnard Bagnis C, Deray G, Baumelou A, Le Quintrec M, Vanherweghem J. Herbs and the kidney. Am J Kidney Dis. 2004;44:1-11 pubmed
    ..It seems critical that caregivers be aware of the potential risk of such often underreported therapy and carefully question their patients about their use of this popular branch of alternative medicine. ..
  33. Ding X, Liang A, Wang J, Xiao Y, Wu Z, Li C, et al. [Nephrotoxicity of Aristolochia manshuriensis and aristolochic acids in mice]. Zhongguo Zhong Yao Za Zhi. 2005;30:1019-22 pubmed
    The acute toxic effects of Aristolochia manshuriensis (GMT) and the total aristolochic acids (TA) were compared in mice with aristolochic acid A (AA) as the dose standard...
  34. Wen Y, Qu L, Li X. Ischemic injury underlies the pathogenesis of aristolochic acid-induced acute kidney injury. Transl Res. 2008;152:38-46 pubmed publisher
  35. Chen L, Mei N, Yao L, Chen T. Mutations induced by carcinogenic doses of aristolochic acid in kidney of Big Blue transgenic rats. Toxicol Lett. 2006;165:250-6 pubmed
    ..These results suggest that AA induces kidney tumors in rats though a mutagenic mechanism of action. ..
  36. Xiao Y, Ge M, Xue X, Wang C, Wang H, Wu X, et al. Hepatic cytochrome P450s metabolize aristolochic acid and reduce its kidney toxicity. Kidney Int. 2008;73:1231-9 pubmed publisher
    ..These results indicate that hepatic P450s play an important role in metabolizing aristolochic acid I into less toxic metabolites and thus have a detoxification role in aristolochic acid I-induced kidney injury. ..
  37. Grollman A, Jelakovic B. Role of environmental toxins in endemic (Balkan) nephropathy. October 2006, Zagreb, Croatia. J Am Soc Nephrol. 2007;18:2817-23 pubmed
    ..Public health authorities in countries harboring this disease are encouraged to reduce the potential for dietary exposure to Aristolochia clematitis...
  38. Chan W, Luo H, Zheng Y, Cheng Y, Cai Z. Investigation of the metabolism and reductive activation of carcinogenic aristolochic acids in rats. Drug Metab Dispos. 2007;35:866-74 pubmed
    The metabolic activation of aristolochic acids (AAs) that have been demonstrated to be mutagenic and carcinogenic was investigated...
  39. Chen T, Guo L, Zhang L, Shi L, Fang H, Sun Y, et al. Gene expression profiles distinguish the carcinogenic effects of aristolochic acid in target (kidney) and non-target (liver) tissues in rats. BMC Bioinformatics. 2006;7 Suppl 2:S20 pubmed
  40. Jong T, Lee M, Hsiao S, Hsai J, Wu T, Chiang S, et al. Analysis of aristolochic acid in nine sources of Xixin, a traditional Chinese medicine, by liquid chromatography/atmospheric pressure chemical ionization/tandem mass spectrometry. J Pharm Biomed Anal. 2003;33:831-7 pubmed
    ..By applying this method to methanol extracts of nine Asarum species, the concentrations of AA-I were found to range from 3.3 ng/mg (Asarum sieboldii) to 3376.9 ng/mg (Asarum crispulatum). ..
  41. Chen Y, Chiang S, Wu H, Kao S, Hsiang C, Ho T, et al. Microarray analysis reveals the inhibition of nuclear factor-kappa B signaling by aristolochic acid in normal human kidney (HK-2) cells. Acta Pharmacol Sin. 2010;31:227-36 pubmed publisher
    ..Our data revealed that AA could suppress NF-kappaB activity in normal human cells, perhaps partially accounting for the reported anti-inflammatory effects of some plants from the genus Aristolochia. ..
  42. Debellé F, Nortier J, Arlt V, De Prez E, Vienne A, Salmon I, et al. Effects of dexfenfluramine on aristolochic acid nephrotoxicity in a rat model for Chinese-herb nephropathy. Arch Toxicol. 2003;77:218-26 pubmed
    ..These functional and histological data suggest that DXF does not enhance AA nephrotoxicity in a rat model for CHN. Further investigations are needed to clarify the mechanism by which DXF may enhance AA-DNA adduct formation...
  43. Nortier J, Martinez M, Schmeiser H, Arlt V, Bieler C, Petein M, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med. 2000;342:1686-92 pubmed
    ..The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high. ..
  44. Chen S, Fan M, Tseng C, Ho Y, Hsu K. Pharmacokinetics and nephrotoxicity of aristolochic acid in rabbits. Toxicon. 2007;50:180-8 pubmed
    b>Aristolochic acids (AAs) which exist in plants of the genus Aristolochia are the toxins responsible for aristolochic acid nephropathy (AAN). To investigate the pharmacokinetics and nephrotoxicity of AAs, rabbits were used in this study...
  45. Arlt V, Pfohl Leszkowicz A, Cosyns J, Schmeiser H. Analyses of DNA adducts formed by ochratoxin A and aristolochic acid in patients with Chinese herbs nephropathy. Mutat Res. 2001;494:143-50 pubmed
    ..These results demonstrate that OTA-related DNA adducts do not play a key role in CHN or CHN-associated urothelial cancer. ..
  46. Yang L, Li X, Wang H. Possible mechanisms explaining the tendency towards interstitial fibrosis in aristolochic acid-induced acute tubular necrosis. Nephrol Dial Transplant. 2007;22:445-56 pubmed
    ..Injury and loss of PTC occurred in AA-ATN, and this may contribute to tubulointerstitial damage, the inability of plerosis and the tendency towards fibrosis in this disease. ..
  47. Liu Q, Wang Q, Yang X, Shen X, Zhang B. Differential cytotoxic effects of denitroaristolochic acid II and aristolochic acids on renal epithelial cells. Toxicol Lett. 2009;184:5-12 pubmed publisher
    b>Aristolochic acids (AAs), naturally occurring nephrotoxins and rodent carcinogens, are commonly found in medicinal plants such as Radix aristolochiae...
  48. Sun D, Feng J, Dai C, Sun L, Jin T, Ma J, et al. Role of peritubular capillary loss and hypoxia in progressive tubulointerstitial fibrosis in a rat model of aristolochic acid nephropathy. Am J Nephrol. 2006;26:363-71 pubmed
    ..Following the reduction of PTCs density and up-regulation of HIF-1alpha, the tubulointerstitial fibrosis area increased. Ischemia and hypoxia are the important causes of severe tubulointerstitial fibrosis in AAN rats. ..
  49. Xue X, Xiao Y, Zhu H, Wang H, Liu Y, Xie T, et al. Induction of P450 1A by 3-methylcholanthrene protects mice from aristolochic acid-I-induced acute renal injury. Nephrol Dial Transplant. 2008;23:3074-81 pubmed publisher
    ..This study was designed to investigate whether P450 1A plays a role in AAI-induced renal injury in C57BL/6 mice...
  50. Balachandran P, Wei F, Lin R, Khan I, Pasco D. Structure activity relationships of aristolochic acid analogues: toxicity in cultured renal epithelial cells. Kidney Int. 2005;67:1797-805 pubmed
    ..AA induced caspase activation was also observed. These cytotoxic data suggest that the nitro and methoxy groups are critical determinants of nephrotoxicologic potency of AA. ..
  51. Ioset J, Raoelison G, Hostettmann K. Detection of aristolochic acid in Chinese phytomedicines and dietary supplements used as slimming regimens. Food Chem Toxicol. 2003;41:29-36 pubmed
    ..fangchi (Aristolochiaceae), known to contain very nephrotoxic and carcinogenic metabolites named aristolochic acids. Several commercial dietary supplements, teas and phytomedicines used as slimming regimens were analysed for ..
  52. Stiborova M, Hajek M, Frei E, Schmeiser H. Carcinogenic and nephrotoxic alkaloids aristolochic acids upon activation by NADPH : cytochrome P450 reductase form adducts found in DNA of patients with Chinese herbs nephropathy. Gen Physiol Biophys. 2001;20:375-92 pubmed
    ..The results presented here are the first report demonstrating a reductive activation of natural nitroaromatic compounds, AA, by NADPH: CYP reductase. ..
  53. Debelle F, Vanherweghem J, Nortier J. Aristolochic acid nephropathy: a worldwide problem. Kidney Int. 2008;74:158-69 pubmed publisher
    ..Finally, despite the Food and Drug Administration's warnings concerning the safety of botanical remedies containing AA, these herbs are still sold via the Internet...