Developmental toxicity of dextromethorphan in zebrafish embryos/larvae.
Dextromethorphan is widely used in over-the-counter cough and cold medications. Its efficacy and safety for infants and young children remains to be clarified. The present study was designed to use zebrafish as a model to investigate the potential toxicity of dextromethorphan during embryonic and larval development. Three sets of zebrafish embryos/larvae were exposed to dextromethorphan at 24, 48 and 72 h post fertilization (hpf), respectively, during the embryonic/larval development. Compared with the 48 and 72 hpf exposure sets, the embryos/larvae in the 24 hpf exposure set showed much higher mortality rates which increased in a dose-dependent manner. Bradycardia and reduced blood flow were observed for the embryos/larvae treated with increasing concentrations of dextromethorphan. Morphological effects of dextromethorphan exposure, including yolk sac and cardiac edema, craniofacial malformation, lordosis, non-inflated swim bladder and missing gill, were also more frequent and severe among zebrafish embryos/larvae exposed to dextromethorphan at 24 hpf. Whether the more frequent and severe developmental toxicity of dextromethorphan observed among the embryos/larvae in the 24 hpf exposure set, as compared with the 48 and 72 hpf exposure sets, is due to the developmental expression of the phase I and phase II enzymes involved in the metabolism of dextromethorphan remains to be clarified. A reverse transcription-polymerase chain reaction analysis, nevertheless, revealed developmental stage-dependent expression of mRNAs encoding SULT3 ST1 and SULT3 ST3, two enzymes previously shown to be capable of sulfating dextrorphan, an active metabolite of dextromethorphan.
Xu
Zheng
Z
Department of Pharmacology, College of Pharmacy, The University of Toledo, Toledo, OH 43606 USA.
Williams
Frederick E
FE
Liu
Ming-Cheh
MC
D000818:Animals; D000996:Antitussive Agents / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced / Q000196:embryology; D019465:Craniofacial Abnormalities / Q000139:chemically induced / Q000196:embryology; D003915:Dextromethorphan / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000196:embryology; D004489:Edema, Cardiac / Q000139:chemically induced / Q000196:embryology; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007814:Larva / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D013723:Teratogens / Q000633:toxicity*; D015017:Yolk Sac / Q000187:drug effects / Q000473:pathology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D000996:Antitussive Agents; D012333:RNA, Messenger; D013723:Teratogens; D029961:Zebrafish Proteins; D003915:Dextromethorphan; C548300:SULT3 sulfotransferase, zebrafish; D015238:Sulfotransferases