Renal toxicity of aristolochic acid in rats as an example of nephrotoxicity testing in routine toxicology

Mengs, U.; Stotzem, C. D.

doi:10.1007/bf01973700

Cited by 104 publications

(59 citation statements)

References 22 publications

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“…High doses of the natural mixture of aristolochic acids I and II induce acute tubular necrosis in animals 30 and humans, 31 but chronic interstitial fibrosis has not been reported. The carcinogenic and mutagenic effects associated with the binding of metabolites of aristolochic acid to DNA have been extensively described in studies in animals and in vitro studies 8,32 and resulted in the classification of aristolochic acid as a genotoxic carcinogen.…”

Section: Discussionmentioning

confidence: 99%

Urothelial Carcinoma Associated with the Use of a Chinese Herb (Aristolochia fangchi)

Nortier,

Martinez,

Schmeiser

et al. 2000

N Engl J Med

972

661

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Section: Discussionmentioning

confidence: 99%

Urothelial Carcinoma Associated with the Use of a Chinese Herb (Aristolochia fangchi)

Nortier,

Martinez,

Schmeiser

et al. 2000

N Engl J Med

972

661

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“…1) For safe clinical use, it is quite necessary to evaluate the toxicity of AF and HAF since relatively high contents of AAs are found in them. Up to now, the pharmacological and toxicological actions of AAs, [4][5][6][16][17][18][19][20] A. manshuriensis [21][22][23] and A. fangchi [24][25][26] were well known, but only one piece of literature could be accessed on the subchronic toxicity of the aqueous extract of AF. 27) Drug processing is a traditional pharmaceutical technology in China, and plays an important role in reducing the toxicity of the traditional drugs.…”

Section: Acute and Subacute Toxicity Of The Extract Of Aristolochiae mentioning

confidence: 99%

Acute and Subacute Toxicity of the Extract of <i>Aristolochiae Fructus</i> and Honey-Fried <i>Aristolochiae Fructus</i> in Rodents

Jie

Huang

Ren

et al. 2014

Biological & Pharmaceutical Bulletin

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Aristolochiae Fructus (AF) and honey-fried Aristolochiae Fructus (HAF) have been used in China for thousands of years as an anti-tussive and expectorant drug. Few clinical cases were reported associated with the toxicity of AF and HAF, although relatively high contents of aristolochic acids (AAs) were found in them. This work was designed to compare the acute and subacute toxicity of AF and HAF in order to provide references for safe clinical use and to evaluate the possibility of reducing toxicity of AF by honey-processing. The extracts of the herb were fed to mice or rats via gastric tube. Various toxic signs and symptoms, body weights, serum biochemical assay, organ weights and histopathology were used to evaluate the toxic effects. The median lethal dose (LD 50 ) of AF and HAF are 34.1 7.2 g/kg/d and 62.6 8.0 g/kg/d with a 95% average trustable probability (p 0.95), respectively. The subacute results showed a dose-dependant relationship of the toxicity of AF and HAF. Even in the high dose groups, only moderate toxicity was observed. Honeyfrying and decoction with water can decrease the contents of AAs, and attenuate the toxic effects of AF. But sufficient attention should be still paid to the safety of AF and HAF due to the existence of AAs. Key wordsacute toxicity; subacute toxicity; Aristolochiae Fructus; honey-fried Aristolochiae Fructus; honey-frying technology; herbal safety Aristolochiae Fructus (AF), the dry-ripe fruit of Aristolochia contorta BGE. or Aristolochia debilis SIEB. et ZUCC., has been used in China for thousands of years as an anti-tussive and expectorant drug.1) Honey-fried AF (HAF) has higher frequency of use than AF in clinic.The herbs and herbal remedies containing aristolochic acids (AAs) have drawn extensive attention because they are associated with the development of a chronic, progressive renal disease, designated as aristolochic acid nephropathy (AAN).2)The AAN case was reported initially in a group of women in Belgium who developed severe renal disease after ingesting slimming pills containing Aristolochia fangchi.3) Now, AAs have been proven to be nephrotoxic, 4-6) carcinogenic [6][7][8] and mutagenic. 8,9) Therefore, most AAs-generating herbs and herbal preparations have been banned in many countries, including China. Some literatures [10][11][12][13][14][15] have reported that AAs contents in herbs were in the following order: A. manshuriensis>A. fangchi>A. Ridix>A. Fructus (AF)>A. Herbra. However, few clinical cases were reported to be associated with the toxicity of AF, AF and HAF were still listed in Chinese Pharmacopoeia (CP).1) For safe clinical use, it is quite necessary to evaluate the toxicity of AF and HAF since relatively high contents of AAs are found in them. Up to now, the pharmacological and toxicological actions of AAs, [4][5][6][16][17][18][19][20] A. manshuriensis [21][22][23] and A. fangchi [24][25][26] were well known, but only one piece of literature could be accessed on the subchronic toxicity of the aqueous extract of AF. 27)Drug processing is a traditio...

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“…Toxicologic studies in mice, rats, and rabbits reveal that treatment with AA is associated with renal tubular damage (Mengs and Stotzem, 1993;Cosyns et al, 2001), interstitial fibrosis (Cosyns et al, 2001;Debelle et al, 2002), and cancer Mengs, 1983Mengs, , 1988Cui et al, 2005). Cosyns et al (2001) used a rabbit model to study the toxicities of AAs by injecting an i.p.…”

mentioning

confidence: 99%

Selective Toxicity of Aristolochic Acids I and II

Shibutani

Dong²,

Suzuki³

et al. 2007

Drug Metabolism and Disposition

138

124

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ABSTRACT: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 fibrosis, and urothelial cancer. To distinguish the component(s) of AA responsible for these varied toxic effects, we administered 2.5 mg/kg/day of AA-I or AA-II for 9 days, either i.p. or p.o., to male C3H/He mice. Tissues were then collected and subjected to biochemical and histopathologic examination. Genotoxicity was assessed by determining quantitatively the level of aristolactam-DNA adducts in various tissues using 32 P-postlabeling/polyacrylamide gel electrophoresis and an internal standard. In the primary target tissues, represented by the renal cortex, medulla, and bladder, we found similar levels of DNA adducts derived from AA-I and AA-II. However, in nontarget tissues, the liver, stomach, intestine, and lung, the levels of aristolactam-DNA adducts derived from AA-I were significantly higher than those derived from AA-II. Histopathologic analysis revealed tubular cell necrosis and interstitial fibrosis in the renal cortex of AA-I-treated mice but only minimal changes in the renal cortex of mice treated with AA-II. We conclude that AA-I and AA-II have similar genotoxic and carcinogenic potential, and, although both compounds are cytotoxic, AA-I is solely responsible for the nephrotoxicity associated with AAN.

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Renal toxicity of aristolochic acid in rats as an example of nephrotoxicity testing in routine toxicology

Cited by 104 publications

References 22 publications

Urothelial Carcinoma Associated with the Use of a Chinese Herb (Aristolochia fangchi)

Urothelial Carcinoma Associated with the Use of a Chinese Herb (Aristolochia fangchi)

Acute and Subacute Toxicity of the Extract of <i>Aristolochiae Fructus</i> and Honey-Fried <i>Aristolochiae Fructus</i> in Rodents

Selective Toxicity of Aristolochic Acids I and II

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