Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers association
Abstract Background Ames test is used worldwide for detecting the bacterial mutagenicity of chemicals. In silico analyses of bacterial mutagenicity have recently gained acceptance by regulatory agencies; however, current in silico models for prediction remain to be improved. The Japan Pharmaceutical...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-09-01
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| Series: | Genes and Environment |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s41021-021-00206-1 |
| _version_ | 1819151491692232704 |
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| author | Atsushi Hakura Takumi Awogi Toshiyuki Shiragiku Atsushi Ohigashi Mika Yamamoto Kayoko Kanasaki Hiroaki Oka Yasuaki Dewa Shunsuke Ozawa Kouji Sakamoto Tatsuya Kato Eiji Yamamura |
| author_facet | Atsushi Hakura Takumi Awogi Toshiyuki Shiragiku Atsushi Ohigashi Mika Yamamoto Kayoko Kanasaki Hiroaki Oka Yasuaki Dewa Shunsuke Ozawa Kouji Sakamoto Tatsuya Kato Eiji Yamamura |
| author_sort | Atsushi Hakura |
| collection | DOAJ |
| description | Abstract Background Ames test is used worldwide for detecting the bacterial mutagenicity of chemicals. In silico analyses of bacterial mutagenicity have recently gained acceptance by regulatory agencies; however, current in silico models for prediction remain to be improved. The Japan Pharmaceutical Manufacturers Association (JPMA) organized a task force in 2017 in which eight Japanese pharmaceutical companies had participated. The purpose of this task force was to disclose a piece of pharmaceutical companies’ proprietary Ames test data. Results Ames test data for 99 chemicals of various chemical classes were collected for disclosure in this study. These chemicals are related to the manufacturing process of pharmaceutical drugs, including reagents, synthetic intermediates, and drug substances. The structure-activity (mutagenicity) relationships are discussed in relation to structural alerts for each chemical class. In addition, in silico analyses of these chemicals were conducted using a knowledge-based model of Derek Nexus (Derek) and a statistics-based model (GT1_BMUT module) of CASE Ultra. To calculate the effectiveness of these models, 89 chemicals for Derek and 54 chemicals for CASE Ultra were selected; major exclusions were the salt form of four chemicals that were tested both in the salt and free forms for both models, and 35 chemicals called “known” positives or negatives for CASE Ultra. For Derek, the sensitivity, specificity, and accuracy were 65% (15/23), 71% (47/66), and 70% (62/89), respectively. The sensitivity, specificity, and accuracy were 50% (6/12), 60% (25/42), and 57% (31/54) for CASE Ultra, respectively. The ratio of overall disagreement between the CASE Ultra “known” positives/negatives and the actual test results was 11% (4/35). In this study, 19 out of 28 mutagens (68%) were detected with TA100 and/or TA98, and 9 out of 28 mutagens (32%) were detected with either TA1535, TA1537, WP2uvrA, or their combination. Conclusion The Ames test data presented here will help avoid duplicated Ames testing in some cases, support duplicate testing in other cases, improve in silico models, and enhance our understanding of the mechanisms of mutagenesis. |
| first_indexed | 2024-12-22T14:34:15Z |
| format | Article |
| id | doaj.art-c58017a903bf4f5db6e48e003410f1b0 |
| institution | Directory Open Access Journal |
| issn | 1880-7062 |
| language | English |
| last_indexed | 2024-12-22T14:34:15Z |
| publishDate | 2021-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Genes and Environment |
| spelling | doaj.art-c58017a903bf4f5db6e48e003410f1b02022-12-21T18:22:40ZengBMCGenes and Environment1880-70622021-09-0143111610.1186/s41021-021-00206-1Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers associationAtsushi Hakura0Takumi Awogi1Toshiyuki Shiragiku2Atsushi Ohigashi3Mika Yamamoto4Kayoko Kanasaki5Hiroaki Oka6Yasuaki Dewa7Shunsuke Ozawa8Kouji Sakamoto9Tatsuya Kato10Eiji Yamamura11Global Drug Safety, Eisai Co., Ltd.Manufacturing Process Development Department, Otsuka Pharmaceutical Co., Ltd.Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd.Process Chemistry Labs, Astellas Pharma Inc.Drug Safety Research Labs, Astellas Pharma Inc.Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd.Toxicology Laboratory, Taiho pharmaceutical Co., Ltd.Toxicology Research Laboratory, Kyorin Pharmaceutical Co., Ltd.Toxicology Research Laboratory, Kyorin Pharmaceutical Co., Ltd.Drug Safety, Taisho Pharmaceutical Co., Ltd.Safety Research Laboratories, Mitsubishi Tanabe Pharma Co.Safety Research Laboratories, Mitsubishi Tanabe Pharma Co.Abstract Background Ames test is used worldwide for detecting the bacterial mutagenicity of chemicals. In silico analyses of bacterial mutagenicity have recently gained acceptance by regulatory agencies; however, current in silico models for prediction remain to be improved. The Japan Pharmaceutical Manufacturers Association (JPMA) organized a task force in 2017 in which eight Japanese pharmaceutical companies had participated. The purpose of this task force was to disclose a piece of pharmaceutical companies’ proprietary Ames test data. Results Ames test data for 99 chemicals of various chemical classes were collected for disclosure in this study. These chemicals are related to the manufacturing process of pharmaceutical drugs, including reagents, synthetic intermediates, and drug substances. The structure-activity (mutagenicity) relationships are discussed in relation to structural alerts for each chemical class. In addition, in silico analyses of these chemicals were conducted using a knowledge-based model of Derek Nexus (Derek) and a statistics-based model (GT1_BMUT module) of CASE Ultra. To calculate the effectiveness of these models, 89 chemicals for Derek and 54 chemicals for CASE Ultra were selected; major exclusions were the salt form of four chemicals that were tested both in the salt and free forms for both models, and 35 chemicals called “known” positives or negatives for CASE Ultra. For Derek, the sensitivity, specificity, and accuracy were 65% (15/23), 71% (47/66), and 70% (62/89), respectively. The sensitivity, specificity, and accuracy were 50% (6/12), 60% (25/42), and 57% (31/54) for CASE Ultra, respectively. The ratio of overall disagreement between the CASE Ultra “known” positives/negatives and the actual test results was 11% (4/35). In this study, 19 out of 28 mutagens (68%) were detected with TA100 and/or TA98, and 9 out of 28 mutagens (32%) were detected with either TA1535, TA1537, WP2uvrA, or their combination. Conclusion The Ames test data presented here will help avoid duplicated Ames testing in some cases, support duplicate testing in other cases, improve in silico models, and enhance our understanding of the mechanisms of mutagenesis.https://doi.org/10.1186/s41021-021-00206-1Ames testMutagenicityBacteriaIn silicoStructure-activity relationshipDerek Nexus |
| spellingShingle | Atsushi Hakura Takumi Awogi Toshiyuki Shiragiku Atsushi Ohigashi Mika Yamamoto Kayoko Kanasaki Hiroaki Oka Yasuaki Dewa Shunsuke Ozawa Kouji Sakamoto Tatsuya Kato Eiji Yamamura Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers association Genes and Environment Ames test Mutagenicity Bacteria In silico Structure-activity relationship Derek Nexus |
| title | Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers association |
| title_full | Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers association |
| title_fullStr | Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers association |
| title_full_unstemmed | Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers association |
| title_short | Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers association |
| title_sort | bacterial mutagenicity test data collection by the task force of the japan pharmaceutical manufacturers association |
| topic | Ames test Mutagenicity Bacteria In silico Structure-activity relationship Derek Nexus |
| url | https://doi.org/10.1186/s41021-021-00206-1 |
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