uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Cell-specific Expression of CYP2A5 in the Mouse Respiratory Tract: Effects of Olfactory Toxicants
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
Show others and affiliations
2003 (English)In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 51, no 11, 1545-1555 p.Article in journal (Refereed) Published
Abstract [en]

We performed a detailed analysis of mouse cytochrome P450 2A5 (CYP2A5) expression by in situ hybridization (ISH) and immunohistochemistry (IHC) in the respiratory tissues of mice. The CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region, with an expression in sustentacular cells, Bowman's gland, and duct cells. In the respiratory and transitional epithelium there was no or only weak expression. The nasolacrimal duct and the excretory ducts of nasal and salivary glands displayed expression, whereas no expression occurred in the acini. There was decreasing expression along the epithelial linings of the trachea and lower respiratory tract, whereas no expression occurred in the alveoli. The hepatic CYP2A5 inducers pyrazole and phenobarbital neither changed the CYP2A5 expression pattern nor damaged the olfactory mucosa. In contrast, the olfactory toxicants dichlobenil and methimazole induced characteristic changes. The damaged Bowman's glands displayed no expression, whereas the damaged epithelium expressed the enzyme. The CYP2A5 expression pattern is in accordance with previously reported localization of protein and DNA adducts and the toxicity of some CYP2A5 substrates. This suggests that CYP2A5 is an important determinant for the susceptibility of the nasal and respiratory epithelia to protoxicants and procarcinogens.

Place, publisher, year, edition, pages
2003. Vol. 51, no 11, 1545-1555 p.
Keyword [en]
CYP2A5, immunohistochemistry, in situ hybridization, olfactory toxicant, dichlobenil, methimazole, olfactory neuroepithelium, Bowman's glands, salivary gland, respiratory metaplasia
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-93785DOI: 10.1177/002215540305101114ISI: 000186696800014PubMedID: 14566026OAI: oai:DiVA.org:uu-93785DiVA: diva2:167374
Available from: 2005-11-25 Created: 2005-11-25 Last updated: 2011-03-10Bibliographically 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

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Bergström, UlrikaBrittebo, Eva
By organisation
Department of Pharmaceutical BiosciencesEnvironmental Toxicology
In the same journal
Journal of Histochemistry and Cytochemistry
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 263 hits
ReferencesLink to record
Permanent link

Direct link