Aristolochic acid is a direct mutagen in Salmonella typhimurium

Robisch, Günter; Schimmer, Oskar; Göggelmann, W.

doi:10.1016/0165-7992(82)90031-8

Cited by 50 publications

(12 citation statements)

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“…2, left panel). Similar activities had been found by Robisch et al 13 for aristolochic acid I (∼0.6 revertants per nmol) and by Schmeiser et al 42. for various mixtures of aristolochic acids I and II (0.7–0.9 revertants per nmol), using slightly different protocols.…”

Section: Resultssupporting

confidence: 83%

“…Several different mammalian enzymes, including human cytochrome P450 (CYP) reductase,10 human CYP1A1 and CYP1A2,11 ram prostaglandin synthase12 and rat DT diaphorase,12 are capable of mediating the reduction of aristolochic acids to DNA‐binding species. Likewise, Salmonella typhimurium contains an endogenous nitroreductase enzyme, which is required for the detection of mutagenic activity of aristolochic acids in this target cell 13, 14, 15. It appears that the reduced product forms a resonance‐stabilized nitrenium ion via intramolecular acylation.…”

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confidence: 99%

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Human sulphotransferases are involved in the activation of aristolochic acids and are expressed in renal target tissue

Meinl

Pabel

Osterloh-Quiroz

et al. 2005

Intl Journal of Cancer

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Use of herbal preparations containing Aristolochia species has led to progressive nephropathy and urothelial cancer in humans. Analysis of DNA adducts formed in human target tissues and studies in animal models have pointed out a major role of the secondary plant metabolites, aristolochic acids, in these effects. Only a minority of the users of Aristolochia-containing products developed nephropathy and cancer, suggesting differences in individual susceptibility. Differences in metabolic activation and inactivation frequently affect the susceptibility towards chemicals. Others have shown that the activation of aristolochic acids to DNA-reactive and mutagenic metabolites requires reduction of their aryl nitro group. The biological activity of numerous nitro-and aminoarenes, after appropriate phase I metabolism, is strongly enhanced in the presence of acetyltransferases or sulphotransferases (SULTs). In the present study, we demonstrate that expression of human SULTs in bacterial and mammalian target cells reinforces the mutagenic activity of aristolochic acids. Using Salmonella typhimurium TA1538 as the recipient organism, we identified the expression of all 12 human SULT forms. SULT1A1 led to the strongest increase in the mutagenicity of aristolochic acids. Some activation was also observed with SULT1B1, but not with the remaining forms. The role of SULT1A1 in the activation of aristolochic acids was corroborated using S. typhimurium TA100-and Chinese hamster V79-derived target cells engineered for expression of human SULT1A1 when compared with control cells. Furthermore, pentachlorophenol, an inhibitor of SULT1A1, strongly reduced the mutagenic effect of aristolochic acids in V79-hCYP2E1-hSULT1A1 cells. Moreover, we demonstrate that SULT1A1 and SULT1B1 are expressed in human kidney using immunoblot analysis, but their levels are substantially lower than in liver. Finally, we discuss the possibility that reactive sulphuric acid conjugates produced in other tissues are transferred to kidney and ureter. ' 2005 Wiley-Liss, Inc.

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Section: Resultssupporting

confidence: 83%

mentioning

confidence: 99%

Human sulphotransferases are involved in the activation of aristolochic acids and are expressed in renal target tissue

Meinl

Pabel

Osterloh-Quiroz

et al. 2005

Intl Journal of Cancer

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“…Robisch et al [35] reported that AA mixture induced reverse mutation in TA100 and TA1537. In addition, AA I and II (1–1000 μ g/plate) were mutagenic to TA98 in the presence or absence of metabolic activation [12, 24, 36].…”

Section: Resultsmentioning

confidence: 99%

In VitroandIn VivoGenotoxicity Assessment ofAristolochia manshuriensisKom.

Hwang

Kim

Cho

et al. 2012

Evidence-Based Complementary and Alternative Medicine

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Arisolochiae species plants containing aristolochic acids I and II (AA I and AA II) are well known to cause aristolochic acid nephropathy (AAN). Recently, there are various approaches to use AAs-containing herbs after the removal of their toxic factors. However, there is little information about genotoxicity of Arisolochiae manshuriensis Kom. (AMK) per se. To obtain safety information for AMK, its genotoxicity was evaluated in accordance with OECD guideline. To evaluate genotoxicity of AMK, we tested bacterial reverse mutation assay, chromosomal aberration test, and micronucleus test. Here, we also determined the amounts of AA I and II in AMK (2.85 ± 0.08 and 0.50 ± 0.02 mg/g extract, resp.). In bacterial reverse mutation assay, AMK dose-dependently increased revertant colony numbers in TA98, TA100 and TA1537 regardless of metabolic activation. AMK increased the incidence of chromosomal aberration in Chinese hamster ovary-K1 cells, but there was no statistically significant difference. The incidences of micronucleus in bone marrow erythrocyte were significantly increased in mice after oral administration of AMK (5000 mg/kg), comparing with those of vehicle group (P < 0.05). The results of three standard tests suggest that the genotoxicity of AMK is directly related to the AAs contents in AMK.

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“…Herbal medicines derived from Aristolochia have been used since ancient times to treat disease (18). However, in the 1980s AA was shown to be a strong carcinogen in rats and, in short-term tests, to be a genotoxic mutagen (19,20,21,22). The US Food and Drug Administration (FDA) has issued warnings regarding the medicinal use of Aristolochia herbals.…”

Section: Aristolochic Acidmentioning

confidence: 99%

p53 mutations as fingerprints for aristolochic acid – an environmental carcinogen in endemic (Balkan) nephropathy

Slade

Moll

Brdar

et al. 2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The activation of protooncogenes and inactivation of tumor suppressor genes are considered to be the main molecular events in the multistep process of carcinogenesis. Mutations of the TP53 tumor suppressor gene have been found in nearly all tumor types and are estimated to contribute to more than 50% of all cancers. Most mutations lead to the synthesis of highly stable, inactive proteins that accumulate in the nucleus of cancer cells. Among the 393 codons of the human p53 gene, 222 are targets of 698 different types of mutations. Alterations of codons 175, 248, 273 and 282 correspond to 19 % of all mutations and are considered general hot spot mutations. Dietary exposure to aristolochic acid (AA), an established nephrotoxin and human carcinogen found in all Aristolochia species was shown to be the causative agent of aristolochic acid nephropathy (previously called Chinese herbs nephropathy). This syndrome is characterized by proximal tubular damage, renal interstitial fibrosis, slow progression to the end stage renal disease and a high prevalence of upper urinary tract urothelial carcinoma (otherwise a highly unusual location). AA preferentially binds to purines in DNA and is associated with a high frequency of A → T transversions in the p53 gene. Rats treated with AA develop A:T → T:A mutations in codon 61. The pathological and clinical features of endemic (Balkan) nephropathy closely resemble those associated with aristolochic acid nephropathy except for the slower progression to end stage renal disease and longer cumulative period before the appearance of urothelial cancer. Recently, we reported the presence of AA-DNA adducts in renal cortex and A → T p53 mutations in tumor tissue of patients from Croatia and Bosnia with endemic nephropathy. These data support the hypothesis that dietary exposure to AA is a major risk factor for endemic (Balkan) nephropathy.

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Aristolochic acid is a direct mutagen in Salmonella typhimurium

Cited by 50 publications

References 3 publications

Human sulphotransferases are involved in the activation of aristolochic acids and are expressed in renal target tissue

Human sulphotransferases are involved in the activation of aristolochic acids and are expressed in renal target tissue

In VitroandIn VivoGenotoxicity Assessment ofAristolochia manshuriensisKom.

p53 mutations as fingerprints for aristolochic acid – an environmental carcinogen in endemic (Balkan) nephropathy

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