Evaluation for a mutagenicity of aristolochic acid by Pig-a and PIGRET assays in rats

Koyama, Naomi; Yonezawa, Yutaka; Nakamura, Michi; Sanada, Hisakazu

doi:10.1016/j.mrgentox.2015.12.004

Cited by 6 publications

(3 citation statements)

References 31 publications

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“…Standardized diet and water were provided ad libitum . Groups of male Wistar rats (∼150–170 g, n = 3/group) at the age of 5 weeks were treated ip with AAI and AAII and their AAI/AAII mixture (1:1) according to treatment protocols described in former studies investigating the metabolism of AA. ,,, Rats were treated with one dose of (i) 20 mg/kg body weight (bw) of AAI, (ii) 20 mg/kg bw of AAII, or (iii) 20 mg/kg bw of AAI plus 20 mg/kg bw of AAII. AAs were dissolved in corn oil at a concentration of 6 mg/mL for AAI and AAII and 12 mg/mL for AAI/AAII mixture.…”

Section: Methodsmentioning

confidence: 99%

In Vivo Metabolism of Aristolochic Acid I and II in Rats Is Influenced by Their Coexposure

Dedı́ková

Bárta

Martínek

et al. 2020

Chem. Res. Toxicol.

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The plant extract aristolochic acid (AA), containing aristolochic acid I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy and Balkan endemic nephropathy, unique renal diseases associated with upper urothelial cancer. Differences in the metabolic activation and detoxification of AAI and AAII and their effects on the metabolism of AAI/AAII mixture in the plant extract might be of great importance for an individual's susceptibility in the development of AA-mediated nephropathies and malignancies. Here, we investigated in vivo metabolism of AAI and AAII after ip administration to Wistar rats as individual compounds and as AAI/AAII mixture using high performance liquid chromatography/electrospray ionization mass spectrometry. Experimental findings were supported by theoretical calculations using density functional theory. We found that exposure to AAI/AAII mixture affected the generation of their oxidative and reductive metabolites formed during Phase I biotransformation and excreted in rat urine. Several Phase II metabolites of AAI and AAII found in the urine of exposed rats were also analyzed. Our results indicate that AAI is more efficiently metabolized in rats in vivo than AAII. Whereas AAI is predominantly oxidized during in vivo metabolism, its reduction is the minor metabolic pathway. In contrast, AAII is mainly metabolized by reduction. The oxidative reaction only occurs if aristolactam II, the major reductive metabolite of AAII, is enzymatically hydroxylated, forming aristolactam Ia. In AAI/AAII mixture, the metabolism of AAI and AAII is influenced by the presence of both AAs. For instance, the reductive metabolism of AAI is increased in the presence of AAII while the presence of AAI decreased the reductive metabolism of AAII. These results suggest that increased bioactivation of AAI in the presence of AAII also leads to increased AAI genotoxicity, which may critically impact AAI-mediated carcinogenesis. Future studies are needed to explain the underlying mechanism(s) for this phenomenon.

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Section: Methodsmentioning

confidence: 99%

In Vivo Metabolism of Aristolochic Acid I and II in Rats Is Influenced by Their Coexposure

Dedı́ková

Bárta

Martínek

et al. 2020

Chem. Res. Toxicol.

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“…Importantly, DNA sequencing results support the phenotype-genotype basis of the assay [Komoto et al, 2011; Byrne et al, 2014; Revollo et al, 2015; Krüger et al, 2016]. Much progress has also been made in regard to the number and types of chemicals investigated in the in vivo Pig-a assay, including structurally related mutagen/non-mutagen pairs [Bemis et al, 2015; Labash et al, 2016], potent clastogens [Bhalli et al, 2013a], and promutagens that must undergo metabolic activation to form DNA-reactive intermediates [Bhalli et al, 2011b and 2013b; Shi et al, 2011; Dertinger et al, 2012; Avlasevich et al, 2014; Stankowski et al, 2015; Kikuzuki et al, 2016; Koyama et al, 2016].…”

Section: Discussionmentioning

confidence: 99%

In vivo pig‐a and micronucleus study of the prototypical aneugen vinblastine sulfate

Avlasevich

Labash

Torous

et al. 2017

Environ and Mol Mutagen

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The Pig-a assay is being used in regulatory studies to evaluate the potential of agents to induce somatic cell gene mutations and an OECD test guideline is under development. A working group involved with establishing the guideline recently noted that representative aneugenic agents had not been evaluated, and to help fill this data gap Pig-a mutant phenotype and micronucleated reticulocyte frequencies were measured in an integrated study design to assess the mutagenic and cytogenetic damage responses to vinblastine sulfate exposure. Male Sprague Dawley rats were treated for twenty-eight consecutive days with vinblastine dose levels from 0.0156 to 0.125 mg/ kg/day. Micronucleated reticulocyte frequencies in peripheral blood were determined at Days 4 and 29, and mutant cell frequencies were determined at Days 24, 15, 29, and 46. Vinblastine affected reticulocyte frequencies, with reductions noted during the treatment phase and increases observed following cessation of treatment. Micronucleated reticulocyte frequencies were significantly elevated at Day 4 in the high dose group. Although a statistically significant increase in mutant reticulocyte frequencies were found for one dose group at a single time point (Day 46), it was not deemed biologically relevant because there was no analogous finding in mutant RBCs, it occurred at the lowest dose tested, and only 1 rat exceeded an upper bound tolerance interval established with historical negative control rats. Therefore, whereas micronucleus induction reflects vinblastine's well-established aneugenic effect on hematopoietic cells, the lack of a Pig-a response indicates that this tubulin-binding agent does not cause appreciable mutagenicity in this same cell type. Environ. Mol. Mutagen. 59:30-37, 2018.V C 2017 Wiley Periodicals, Inc.

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“…Moreover, these herbs can be used as raw materials of some drug homologous and healthy foods, and even dietary supplements [3][4][5]. However, it has been reported that AA showed toxicity to humans owing to carcinogenesis [2,[6][7][8], nephrotoxicity [9][10][11], and mutagenicity [9,12]. Some cases reported that the intake of slimming products containing AA resulted in nephropathy [13,14].…”

Section: Introductionmentioning

confidence: 99%

Preparation of Anti-Aristolochic Acid I Monoclonal Antibody and Development of Chemiluminescent Immunoassay and Carbon Dot-Based Fluoroimmunoassay for Sensitive Detection of Aristolochic Acid I

Chen

Zhang

et al. 2021

Foods

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Aristolochic acid (AA) toxicity has been shown in humans regarding carcinogenesis, nephrotoxicity, and mutagenicity. Monitoring the AA content in drug homologous and healthy foods is necessary for the health of humans. In this study, a monoclonal antibody (mAb) with high sensitivity for aristolochic acid I (AA-I) was prepared. Based on the obtained mAb, a chemiluminescent immunoassay (CLEIA) against AA-I was developed, which showed the 50% decrease in the RLUmax (IC50) value of 1.8 ng/mL and the limit of detection (LOD) of 0.4 ng/mL. Carbon dots with red emission at 620 nm, namely rCDs, were synthesized and employed in conventional indirect competitive enzyme-linked immunosorbent assay (icELISA) to improve the assay sensitivity of a fluoroimmunoassay (FIA). Oxidized 3,3′′,5,5′′-tetramethylbenzidine dihydrochloride (oxTMB) can quench the emission of the rCDs through the inner-filter effect; therefore, the fluorescence intensity of rCDs can be regulated by the concentration of mAb. As a result, the assay sensitivity of FIA was improved by five-fold compared to CLEIA. A good relationship between the results of the proposed assays and the standard ultra-high performance liquid chromatography-triple quadrupole mass spectrometer (UPLC-QQQ-MS/MS) of real samples indicated good accuracy and practicability of CLEIA and FIA.

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Evaluation for a mutagenicity of aristolochic acid by Pig-a and PIGRET assays in rats

Cited by 6 publications

References 31 publications

In Vivo Metabolism of Aristolochic Acid I and II in Rats Is Influenced by Their Coexposure

In Vivo Metabolism of Aristolochic Acid I and II in Rats Is Influenced by Their Coexposure

In vivo pig‐a and micronucleus study of the prototypical aneugen vinblastine sulfate

Preparation of Anti-Aristolochic Acid I Monoclonal Antibody and Development of Chemiluminescent Immunoassay and Carbon Dot-Based Fluoroimmunoassay for Sensitive Detection of Aristolochic Acid I

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