Evaluation of a single-dose PIGRET assay for acetaminophen in rats compared with the RBC Pig-a assay

Suzuki, Yuta; Goto, Ken; Nakayama, Yoshihiro; Saratani, Masatoshi; Takata, Takuya; Okamoto, Takezo; Okazaki, Shuzo

doi:10.1016/j.mrgentox.2016.02.007

Cited by 3 publications

(2 citation statements)

References 25 publications

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“…There were no statistically significant or dose‐related increases in mutant phenotype RET (CD59‐negative RETs) or RBC (CD59‐negative RBCs) frequencies (Figure 1) indicative of lack of a Pig‐a gene mutation up to 1,000 mg·kg −1 ·day −1 analyzed at multiple time points up to 29 days of dosing and following a 28‐day recovery period. These findings are in line with the current literature (Suzuki et al ., 2016) in which no changes in the Pig‐a mutant frequency in peripheral blood of male Sprague Dawley rats were observed when treated with a single dose of acetaminophen by oral gavage at doses up to 2,000 mg·kg −1 ·day −1 and evaluated pre‐treatment and 1, 2 and 4 weeks post‐treatment. Moreover, no changes in %RET were observed in any group related to the treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Table 1 within theGollapudia et al, 2015 publication) and the outcome of the trial was published byGollapudia et al, 2015. The study data of the 41 compounds tested in the Pig-a assay in support of this trial are slowly being published and this paper describing the results of acetaminophen is one of them. A similar type of collaborative Pig-a validation study was conducted by the Mammalian Mutagenicity Study Group of the Japanese Environmental Mutagen Society and acetaminophen was also selected as one of the test compounds(Suzuki et al, 2016), albeit data were generated following only single oral treatment administration. It is important to note that a Pig-a Database has been established to make these data available to stakeholders (https://www.pharmacy.…”

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Testing of acetaminophen in support of the international multilaboratory in vivo rat Pig‐a assay validation trial

Leede

Weiner

Doninck

et al. 2020

Environ and Mol Mutagen

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Acetaminophen, a nonmutagenic compound as previously concluded from bacteria, in vitro mammalian cell, and in vivo transgenic rat assays, presented a good profile as a nonmutagenic reference compound for use in the international multilaboratory Pig‐a assay validation. Acetaminophen was administered at 250, 500, 1,000, and 2,000 mg·kg−1·day−1 to male Sprague Dawley rats once daily in 3 studies (3 days, 2 weeks, and 1 month with a 1‐month recovery group). The 3‐Day and 1‐Month Studies included assessments of the micronucleus endpoint in peripheral blood erythrocytes and the comet endpoint in liver cells and peripheral blood cells in addition to the Pig‐a assay; appropriate positive controls were included for each assay. Within these studies, potential toxicity of acetaminophen was evaluated and confirmed by inclusion of liver damage biomarkers and histopathology. Blood was sampled pre‐treatment and at multiple time points up to Day 57. Pig‐a mutant frequencies were determined in total red blood cells (RBCs) and reticulocytes (RETs) as CD59‐negative RBC and CD59‐negative RET frequencies, respectively. No increases in DNA damage as indicated through Pig‐a, micronucleus, or comet endpoints were seen in treated rats. All positive controls responded as appropriate. Data from this series of studies demonstrate that acetaminophen is not mutagenic in the rat Pig‐a model. These data are consistent with multiple studies in other nonclinical models, which have shown that acetaminophen is not mutagenic. At 1,000 mg·kg−1·day−1, Cmax values of acetaminophen on Day 28 were 153,600 ng/ml and 131,500 ng/ml after single and repeat dosing, respectively, which were multiples over that of clinical therapeutic exposures (2.6–6.1 fold for single doses of 4,000 mg and 1,000 mg, respectively, and 11.5 fold for multiple dose of 4,000 mg) (FDA 2002). Data generated were of high quality and valid for contribution to the international multilaboratory validation of the in vivo Rat Pig‐a Mutation Assay.

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confidence: 99%

Testing of acetaminophen in support of the international multilaboratory in vivo rat Pig‐a assay validation trial

Leede

Weiner

Doninck

et al. 2020

Environ and Mol Mutagen

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The PIGRET assay, a method for measuring Pig-a gene mutation in reticulocytes, is reliable as a short-term in vivo genotoxicity test: Summary of the MMS/JEMS-collaborative study across 16 laboratories using 24 chemicals

Kimoto

Horibata

Miura

et al. 2016

Mutation Research/Genetic Toxicology and Environmental Mutagene

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The in vivo mutation assay using the X-linked phosphatidylinositol glycan class A gene (Pig-a in rodents, PIG-A in humans) is a promising tool for evaluating the mutagenicity of chemicals. Approaches for measuring Pig-a mutant cells have focused on peripheral red blood cells (RBCs) and reticulocytes (RETs) from rodents. The recently developed PIGRET assay is capable of screening >1×10 RETs for Pig-a mutants by concentrating RETs in whole blood prior to flow cytometric analysis. Additionally, due to the characteristics of erythropoiesis, the PIGRET assay can potentially detect increases in Pig-a mutant frequency (MF) sooner after exposure compared with a Pig-a assay targeting total RBCs (RBC Pig-a assay). In order to test the merits and limitations of the PIGRET assay as a short-term genotoxicity test, an interlaboratory trial involving 16 laboratories was organized by the Mammalian Mutagenicity Study Group of the Japanese Environmental Mutagenicity Society (MMS/JEMS). First, the technical proficiency of the laboratories and transferability of the assay were confirmed by performing both the PIGRET and RBC Pig-a assays on rats treated with single doses of N-nitroso-N-ethylurea. Next, the collaborating laboratories used the PIGRET and RBC Pig-a assays to assess the mutagenicity of a total of 24 chemicals in rats, using a single treatment design and mutant analysis at 1, 2, and 4 weeks after the treatment. Thirteen chemicals produced positive responses in the PIGRET assay; three of these chemicals were not detected in the RBC Pig-a assay. Twelve chemicals induced an increase in RET Pig-a MF beginning 1 week after dosing, while only 3 chemicals positive for RBC Pig-a MF produced positive responses 1 week after dosing. Based on these results, we conclude that the PIGRET assay is useful as a short-term test for in vivo mutation using a single-dose protocol.

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A comprehensive weight of evidence assessment of published acetaminophen genotoxicity data: Implications for its carcinogenic hazard potential

Kirkland¹,

Kovochich

et al. 2021

Regulatory Toxicology and Pharmacology

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Evaluation of a single-dose PIGRET assay for acetaminophen in rats compared with the RBC Pig-a assay

Cited by 3 publications

References 25 publications

Testing of acetaminophen in support of the international multilaboratory in vivo rat Pig‐a assay validation trial

Testing of acetaminophen in support of the international multilaboratory in vivo rat Pig‐a assay validation trial

The PIGRET assay, a method for measuring Pig-a gene mutation in reticulocytes, is reliable as a short-term in vivo genotoxicity test: Summary of the MMS/JEMS-collaborative study across 16 laboratories using 24 chemicals

A comprehensive weight of evidence assessment of published acetaminophen genotoxicity data: Implications for its carcinogenic hazard potential

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