Albendazole causes stage-dependent developmental toxicity and is deactivated by a mammalian metabolization system in a modified zebrafish embryotoxicity test

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2012-08, Vol.34 (1), p.31-42
• Main Authors: Mattsson, Anna, Ullerås, Erik, Patring, Johan, Oskarsson, Agneta
• Format: Article
• Language: English
• Subjects: Albendazole; Albendazole - pharmacokinetics; Albendazole - toxicity; Animals; Anthelmintics - pharmacokinetics; Anthelmintics - toxicity; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Cytochrome P450 Family 2; Danio rerio; Developmental toxicity; Embryo, Nonmammalian - abnormalities; Embryo, Nonmammalian - drug effects; Embryo, Nonmammalian - physiology; Embryology: invertebrates and vertebrates. Teratology; Embryonic Development - drug effects; Environmental Health and Occupational Health; Freshwater; Fundamental and applied biological sciences. Psychology; Head - abnormalities; Heart - physiology; Heart Defects, Congenital; Malformations; Medical sciences; Metabolism; Microsomes, Liver - metabolism; Miljömedicin och yrkesmedicin; Pharmacology. Drug treatments; Rats; Steroid 21-Hydroxylase - metabolism; Tail - abnormalities; Teratology. Teratogens; Toxicology; Zebrafish; Zebrafish - abnormalities; Zebrafish - physiology
• ISSN: 0890-6238; 1873-1708; 1873-1708
• DOI: 10.1016/j.reprotox.2012.02.007

► The zebrafish embryo toxicity test with an external metabolization system was further developed and additional testing time points with extended exposure durations were included. ► The anthelmintic drug albendazole caused stage dependent toxic effects in zebrafish embryos. ► Albendazole was efficiently metabolized and deactivated by the external metabolization system. The zebrafish embryotoxicity test has previously been combined with an external metabolic activation system (MAS) to assess developmental toxicity of metabolites produced by maternal metabolism. Due to toxicity of MAS the exposure was limited to one early and short period. We have modified the method and included additional testing time points with extended exposure durations. Using the anthelmintic drug albendazole as a model substance, we demonstrated stage-dependent toxic effects at three windows of zebrafish embryo development, i.e. 2–3, 12–14 and 24–28h post fertilization, and showed that MAS, by metabolic deactivation, reduced the toxicity of albendazole at all time points. Chemical analysis confirmed that albendazole was efficiently metabolized by MAS to the corresponding sulfoxide and sulfone, which are non-toxic to zebrafish embryos. To conclude, the modified zebrafish embryotoxicity test with MAS can be expanded for assessment of metabolites at different developmental stages.