Evaluation of olfactory and auditory system effects of the antihyperthyroid drug carbimazole in the Long-Evans rat.
Carbimazole (2-carbethoxythio-1-methylimidazole) is a thiocarbamide drug used in the treatment of hyperthyroidism in humans. Side effects associated with carbimazole treatment are reported to include impaired taste, impaired olfaction, and hearing loss. The structurally similar antihyperthyroid drug methimazole (1-methyl-2-mercaptoimidazole), also reportedly associated with impaired taste and olfaction in humans, has recently been demonstrated by this laboratory to be an olfactory toxicant by both the oral and intraperitoneal routes of exposure in rodents. A systematic evaluation of sensory system effects of these compounds, either in rodents or humans, is not available in the literature. Male Long-Evans rats were used to evaluate the auditory and olfactory toxicity of carbimazole by two routes of exposure. Histopathological evaluation of nasal cavities from rats administered carbimazole via i.p. and oral routes revealed olfactory mucosal damage and early evidence of repair; a no-observed effect level (NOEL) of 100 mg/kg was observed for orally administered carbimazole. Further, these studies demonstrate evidence for the generation of the olfactory toxic metabolites of carbimazole by the olfactory mucosa itself, as incubation of carbimazole with an olfactory S9 preparation resulted in NADPH-dependent degradation of carbimazole. Evaluation of the auditory startle response in carbimazole-treated rats revealed no deficits, demonstrating that carbimazole does not cause a global loss of hearing in rats.
Department of Molecular and Cellular Physiology, University of Cincinnati, OH 45267-0576, USA. gentermb@popmail.uc.edu
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D000284:Administration, Oral; D000818:Animals; D013956:Antithyroid Agents / Q000633:toxicity*; D001303:Auditory Cortex / Q000187:drug effects* / Q000473:pathology; D002231:Carbimazole / Q000378:metabolism / Q000633:toxicity*; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009498:Neurotoxins / Q000633:toxicity; D009570:Nitriles / Q000633:toxicity; D019055:No-Observed-Adverse-Effect Level; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects*; D013194:Staining and Labeling
D013956:Antithyroid Agents; D009498:Neurotoxins; D009570:Nitriles; C008110:3,3'-iminodipropionitrile; D002231:Carbimazole