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Toxicant-induced ER-stress and Caspase Activation in the Olfactory Mucosa
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2005 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 79, no 10, 561-570 p.Article in journal (Refereed) Published
Abstract [en]

The potent olfactory toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO(2)) induces rapid cell death and long-term metaplastic changes in the olfactory regions of rodents. The damage is related to a tissue-specific and extensive cytochrome P450 (CYP)-mediated metabolic activation of the compound to reactive intermediates. The aim of the present study was to examine the early, cell-specific changes leading to cell death in the olfactory mucosa of mice exposed to 2,6-diClPh-MeSO(2). We have examined the expression of the ER-specific stress protein GRP78, the presence of secretory glycoproteins, and the cellular activation of the initiator caspase 12 and the downstream effector caspase 3. 2,6-DiClPh-MeSO(2) induced rapid and cell-specific expression of GRP78, and activation of caspases 12 and 3 in the Bowman's glands. No similar early onset changes in the neuroepithelium were observed. Based on these results, we propose that extensive lesions are initiated in the Bowman's glands and that the metabolic activation of 2,6-diClPh-MeSO(2) elicits ER-stress response and subsequent apoptotic signaling at this site. Since most of the Bowman's glands had oncotic morphology, the results suggest that the terminal phase of apoptosis was blocked and that these glands finally succumb to other routes of cell death.

Place, publisher, year, edition, pages
2005. Vol. 79, no 10, 561-570 p.
Keyword [en]
olfactory mucosa, stress protein, caspase 3, caspase 12, chlorinated benzene
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-93787DOI: 10.1007/s00204-005-0670-8PubMedID: 15902419OAI: oai:DiVA.org:uu-93787DiVA: diva2:167376
Available from: 2005-11-25 Created: 2005-11-25 Last updated: 2011-03-09Bibliographically approved
In thesis
1. Tissue-Selective Activation and Toxicity of Substituted Dichlorobenzenes: Studies on the Mechanism of Cell Death in the Olfactory Mucosa
Open this publication in new window or tab >>Tissue-Selective Activation and Toxicity of Substituted Dichlorobenzenes: Studies on the Mechanism of Cell Death in the Olfactory Mucosa
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The nasal passages are constantly exposed to both air- and bloodborne foreign compounds. In particular, the olfactory mucosa is demonstrated to be susceptible to a variety of drugs and chemicals. In this thesis, mechanisms involved in tissue-selective toxicity in the olfactory mucosa of rodents have been investigated using the olfactory toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) as a model compound. Comparative studies were performed with the non-toxic 2,5-dichlorophenyl methylsulphone (2,5-diClPh-MeSO2) and the reasons for the strikingly different toxicity were investigated.

A strong bioactivation and protein adduction of 2,6-diClPh-MeSO2 in olfactory microsomes and S9-fractions of rodents was demonstrated. In contrast, no significant metabolic activation of 2,5-diClPh-MeSO2 was observed and the bioactivation in the liver for both chlorinated isomers was negligible. In vitro studies with recombinant yeast cell microsomes expressing mouse cytochrome P450 2A5 (CYP2A5) demonstrated a metabolic activation of 2,6-diClPh-MeSO2. The 2,6-diClPh-MeSO2-induced lesions and CYP2A5 expression preferentially occurred in Bowman’s glands and sustentacular cells of the olfactory mucosa. A significant depletion of glutathione (GSH) in the olfactory mucosa was demonstrated in vivo, while no changes were observed in the liver. There was a rapid induction of the endoplasmic reticulum (ER)-specific chaperone Grp78, activation of the ER-specific caspase-12 and the downstream caspase-3 in the Bowman’s glands. Electron microscopy revealed swelling of ER and mitochondria and a lost integrity of the Bowman’s glands.

Based on these results, the proposed mechanism for 2,6-diClPh-MeSO2-induced toxicity in the olfactory mucosa is bioactivation by CYP2A5 into a reactive intermediate causing protein adduction and GSH-depletion. This is initiating a sequence of downstream events of ER-stress, changes in ion homeostasis, ultrastructural organelle disruption and apoptotic signalling. In spite of the initial apoptotic signals, the terminal phase of apoptosis seemed to be blocked and necrotic features occurred. The predominant expression of CYP2A5 in the olfactory mucosa is proposed to play a key role for the tissue- and cell-specific toxicity induced by 2,6-diClPh-MeSO2.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 59 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 23
Toxicology, tissue-selective toxicity, bioactivation, olfactory mucosa, substituted dichlorobenzenes, Bowman's glands, sustentacular cells, ER stress, Grp78, caspase-12, caspase-3, CYP2A5, protein adduction, nasal toxicity, Toxikologi
National Category
Pharmacology and Toxicology
urn:nbn:se:uu:diva-6161 (URN)91-554-6408-4 (ISBN)
Public defence
2005-12-16, B41, BMC, Uppsala, 13:15
Available from: 2005-11-25 Created: 2005-11-25Bibliographically approved

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