title: Evaluation of 4,4'-diaminodiphenyl ether in the rat comet assay: Part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of in vivo rat alkaline comet assay.
abstract: As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay, 4,4'-diaminodiphenyl ether (DPE), a known rodent genotoxic carcinogen, was tested in this laboratory. Sprague Dawley rats (7-9 weeks of age) were given three oral doses of DPE, 24 and 21 h apart and liver or stomach sampled 3h after the final dose. Under the conditions of the test, no increases in DNA damage in liver and stomach were observed with DPE (up to 200 mg/kg/day). A dose-dependent decrease in DNA migration, compared to vehicle controls, was noted for DPE in rat stomach. Further analysis is required to elucidate fully whether this decrease is a consequence of the mode of action or due to the toxicity of DPE. What is perhaps surprising is the inability of the comet assay to detect a known rat genotoxic carcinogen in liver. Further investigation is needed to clarify whether this apparent lack of response results from limited tissue exposure or metabolic differences between species. This finding highlights a need for careful consideration of study design when evaluating assay performance as a measure of in vivo genotoxicity.
authors.affiliation: Genetic Toxicology, Drug Safety And Metabolism, AstraZeneca R&D, Unit 310, Darwin Building, Cambridge Science Park CB4 0WG, United Kingdom. Electronic address: catherine.priestley@astrazeneca.com.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Priestley
authors.affiliation: Genetic Toxicology, Drug Safety And Metabolism, AstraZeneca R&D, Unit 310, Darwin Building, Cambridge Science Park CB4 0WG, United Kingdom.
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Walker
authors.affiliation: Genetic Toxicology, Drug Safety And Metabolism, AstraZeneca R&D, Unit 310, Darwin Building, Cambridge Science Park CB4 0WG, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: O'Donovan
authors.affiliation: Genetic Toxicology, Drug Safety And Metabolism, AstraZeneca R&D, Unit 310, Darwin Building, Cambridge Science Park CB4 0WG, United Kingdom.
authors.forename: Ann T
authors.initials: AT
authors.lastname: Doherty
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D020552:Comet Assay / Q000379:methods*; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects; D008297:Male; D010647:Phenyl Ethers / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013270:Stomach / Q000187:drug effects
chemical_list: D002273:Carcinogens; D010647:Phenyl Ethers; C015126:di-(4-aminophenyl)ether
keywords: 4,4′-diaminodiphenyl ether; In vivo rat comet assay; JaCVAM validation study