title: Zinc gluconate toxicity in wild-type vs. MT1/2-deficient mice.
abstract: Previous studies have suggested that oral zinc supplementation can help reduce the duration of the common cold; however, the use of intranasal (IN) zinc is strongly associated with anosmia, or the loss of the sense of smell, in humans. Prior studies from this lab showed that upregulation of metallothioneins (MT) is a rapid and robust response to zinc gluconate (ZG). Therefore, we assessed the role of MT in the recovery of nasal epithelial damage resulting from IN zinc administration. The main studies in this investigation used a high dose of ZG (170mM) to ensure ablation of the olfactory mucosa, so that the progression of histological and functional recovery could be assessed. In vivo studies using wild-type, MT1/2 knockout mice (MT KO), and heterozygotes administered ZG by IN instillation showed profound loss of the olfactory mucosa in the nasal cavity. Recovery was monitored, and a lower percentage of the MT KO mice were able to smell 28 d after treatment; however, no significant difference was observed in the rate of cell proliferation in the basal layer of the olfactory epithelium between MT KO and wild-type mice. A lower concentration of ZG (33mM), equivalent to that found in homeopathic IN ZG preparations, also caused olfactory epithelial toxicity in mice. These studies suggest that the use of zinc in drug formulations intended for IN administration in humans must be carefully evaluated for their potential to cause olfactory functional deficits.
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, United States.
authors.forename: Heidi
authors.initials: H
authors.lastname: Hsieh
authors.affiliation: Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267-0557, United States; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Horwath
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, United States. Electronic address: Marybeth.genter@uc.edu.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Genter
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005942:Gluconates / Q000008:administration & dosage / Q000633:toxicity*; D053511:Matrix Metalloproteinase 14 / Q000172:deficiency* / Q000235:genetics; D053517:Matrix Metalloproteinase 15 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D000857:Olfaction Disorders / Q000139:chemically induced* / Q000235:genetics*; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D013844:Thiazoles
chemical_list: C558129:2-(3-chloro-4-fluorophenyl)isothiazol-3-one; D005942:Gluconates; D018809:Proliferating Cell Nuclear Antigen; D013844:Thiazoles; D053517:Matrix Metalloproteinase 15; D053511:Matrix Metalloproteinase 14; C030691:gluconic acid
keywords: Intranasal; Metallothionein; Olfactory; Olfactory behavior; Zinc