ARISTOLOCHIC ACID

341.27

345.04700

206-238-3

DTXSID70217421

142.18000

2.98160

yellow powder

260-265 °C

DMSO: soluble

2-8°C

Crystals from dimethylformamide and ethanol, ethanol, or methanol/ether. /Aristolochic acid I/

UN 1544 6.1/PG 3

3

25

7-35-45

CF3325000

T

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Arlt VM et al; Aristolochic Acid as a Probably Human Cancer Hazard in Herbal Remedies: A Review; Mutagenesis 17 (4): 265-77 (2002)

In this study the development of aristolochic acid (AA) induced tumors in rats with and without diallyl sulfide (DAS) was studied. Experiments were also conducted to establish the effects of DAS administration on AA-derived DNA single-stranded regions and DNA adduct formation in the forestomach of such animals. Forestomach, urinary bladder and thymus tumors were induced in male BD-6 rats after oral treatment for 12 weeks with AA (2 x 10 mg/kg/week). Administration of 150 mg/kg DAS intragastrically 4 h prior to AA treatment reduced significantly the number of rats that developed forestomach tumors (6-9 months after the start of experiment). The incidence of AA-induced forestomach tumors was 10% (two out of 20 rats) after co-administration of DAS and 60% (12 out of 20 animals) when AA was administered alone. The high dose of DAS (2 x 150 mg/kg) markedly inhibited the formation of squamous cell carcinomas in the forestomach. However, the thioether did not prevent the formation of forestomach and urinary bladder papillomatosis. Additionally, DAS co-administration decreased the accumulation of single-stranded regions in rat forestomach DNA. Using the nuclease P1 enhancement method of the 32P-postlabeling assay, a decrease in the level of AA-derived adducts was also detected after co-administration of DAS. We conclude that the decrease of DNA damage after DAS co-administration is associated with the delay in conversion of papillomas to malignant forestomach tumors.

LD50 Mouse (male) iv 38.4 mg/kg /Aristolochic Acid I/|LD50 Mouse (female) iv 70.1 mg/kg /Aristolochic Acid I/|LD50 Mouse ip 14.3 mg/kg|LD50 Mouse (male) oral 55.9 mg/kg /Aristolochic Acid I/|For more Non-Human Toxicity Values (Complete) data for ARISTOLOCHIC ACIDS (9 total), please visit the HSDB record page.

Aristolochic acids are alkaloid components of a wide range of species of the family Aristolochiaceae.

Aristolochic acid I (purity not specified) was given by infusion to 20 patients having various malignant tumors, at different dose schedules ranging from 0.1 mg/kg body weight per day for five days to a single dose of 2 mg/kg body weight. The compound was too toxic to the kidneys for further trial. /Aristolochic Acid I/

In an extensive study following oral administration of aristolochic acids I and II to male Wistar rats (pure compounds given; 3 mg), the following metabolites were detected in urine and feces: from aristolochic acid I -- aristolactam I, aristolactam Ia, aristolochic acid Ia, aristolic acid I and 3,4-methylenedioxy-8-hydroxy-1-phenanthrenecarboxylic acid; from aristolochic acid II -- aristolactam II, aristolactam Ia and 3,4-methylenedioxy-1-phenanthrenecarboxylic acid. /Aristolochic Acid I and II/|... Six healthy volunteers were given a daily dose (presumably oral but not explicitly state) of 0.9 mg of a mixture of aristolochic acids I and II (ratio not specified) for several days, and 24 hour urine samples from day 3 of this trial were analysed for metabolites. The only metabolites detected were aristolactam I (metabolite of aristolochic acid I) and aristolactam II (metabolite of aristolochic acid II). The percentage conversions to these two metabolites were not reported. This contradicts and earlier report of oral absorption of aristolochic acid in humans resulting in the compound(s) being excreted unchanged in urine, bile, breast milk and cerebrospinal fluid.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|Presentation depends on the active toxic agent. In most cases, vomiting, abdominal pain, and diarrhea occur within 60 to 90 minutes of significant ingestion. With some toxins, severe gastroenteritis may result in massive fluid and electrolyte loss. ... Maintain open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, arrhythmias, and hypotension if they occur. Replace fluid loss caused by gastroenteritis with intravenous crystalloid solutions. ... Administer activated charcoal if available ... Gastric emptying is not necessary if activated charcoal is given promptly. /Plants and Herbal Medicines: Group 1/

/HUMAN EXPOSURE STUDIES/ Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic. The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated. Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46%; 95% confidence interval, 29 to 62%): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma. The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.|/CASE REPORTS/ Mild to moderate atypia and atypical hyperplasia of the urothelium were detected in three women in Brussels, Belgium, who had undergone nephroureterectomies as part of a transplantation program. All three cases of end-stage renal disease were attributed to the use of Chinese herbs containing aristolochic acids. One of the three women developed, 12 months after transplantation, at the age of 25 years, two papillary tumors of the posterior bladder wall, histologically classified as low-grade transitional-cell carcinomas, without invasion. Microscopic transitional-cell carcinomas of low-to- intermediate grade were also detected in the two ureters (right and remnant distal part of left ureter) and in the right pelvis.|/CASE REPORTS/ At least 100 cases of extensive interstitial fibrosis of the kidneys were observed in Belgium in women who had followed a weight-loss regimen that included the use of Chinese herbs. The possible relation between the renal disease and these Chinese herbs was investigated. It was shown that the prescribed Chinese herb called Stephania tetrandra was, in fact, inadvertently replaced by another Chinese herb, namely Aristolochia fangchi in the powdered extracts delivered in Belgium and in France.|/CASE REPORTS/ A bilateral multifocal transitional-cell urothelial carcinoma occurring six years after the onset of end-stage renal disease was described in one of two cases of Chinese herbal nephropathy in the United Kingdom related to aristolochic acid from Aristolochia manshuriensis contained in Mu Tong.|For more Human Toxicity Excerpts (Complete) data for ARISTOLOCHIC ACIDS (7 total), please visit the HSDB record page.

Aristolochic Acids

Aristolochic acids are alkaloid components of a wide range of species of the family Aristolochiaceae.

Aristolochic acids I and II have been determined in several samples of medicinal plants and slimming products using HPLC. The major component was aristolochic acid I in Aristolochia fangchi and the level ranged from 437 to 668 ppm (mg/kg). Aristolochic acid II was the major component in Aristolochia contorta, at levels ranging from less than 1 to 115 ppm (mg/kg). Twelve out of 16 samples of slimming pills and powders contained aristolochic acids I and/or II. The major component in most slimming products was aristolochic acid II and the level ranged from less than 1 to 148 ppm.|A procedure based on an extraction method used in Germany for the determination of aristolochic acids in botanical products has been developed and applied to a variety of botanicals and botanical-containing dietary supplements. Aristolochic acids are extracted from the sample matrix with aqueous methanol/formic acid. The concentration of aristolochic acids in the extract is determined by gradient high-performance liquid chromatography (HPLC) with UV absorption detection at 390 nm and their identity is confirmed by liquid chromatography/mass spectrometry using either an ion-trap mass spectrometer or a triple quadrupole mass spectrometer. The quantitation limit is equivalent to 1.7 ug/g in solid samples and 0.14 ug/ml in liquid samples.|An HPLC procedure with a silica gel RP-18 reversed-phase column to determine aristolochic acids I and II in medicinal plants and slimming products. The recovery of these two compounds in medicinal plants and slimming products by extracting with methanol and purifying through a PHP-LH-20 (piperidinohydroxypropyl Sephadex LH-20) column was better than 90%.|Targeted liquid chromatography/serial mass spectrometry (LC/MS/MS) analysis, using a quadrupole ion-trap mass spectrometer, permitted the detection of aristolochic acids I and II in crude 70% methanol extracts of multi-component herbal remedies without any clean-up or concentration stages. The best ionization characteristics were obtained using atmospheric pressure chemical ionization (APCI) and by including ammonium ions in the mobile phase. Limits of detection for aristolochic acids were influenced by the level of interference due to other components in the sample matrix. They were determined to be between 250 picogram and 2.5 nanogram on-column within a matrix containing compounds extracted from 2 mg of herbal remedy.|For more Analytic Laboratory Methods (Complete) data for ARISTOLOCHIC ACIDS (6 total), please visit the HSDB record page.