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Isomer-specific Bioactivation and Toxicity of Dichlorophenyl Methylsulphone in Rat Olfactory Mucosa
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.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2003 (English)In: Toxicologic pathology (Print), ISSN 0192-6233, E-ISSN 1533-1601, Vol. 31, no 4, 364-372 p.Article in journal (Refereed) Published
Abstract [en]

This study aimed to explain the isomer- and site-specific toxic effects of dichlorophenyl methylsulphone in the olfactory mucosa of rats. A single ip dose of the 2,6-chlorinated isomer (16 or 65 mg/kg) induced necrosis preferentially in the Bowman's glands and neuroepithelium in the dorsomedial part of the olfactory region. Only minor damage occurred at this site in rats dosed with the 2,5-chlorinated isomer (65 mg/kg). A strong concentration- and time-dependent covalent binding of the C-14-labeled 2,6-isomer to rat olfactory microsomes was demonstrated. In contrast, no significant covalent binding of the C-14-labeled 2,5-isomer was observed. The cytochrome P450 (CYP) inhibitors metyrapone, tranylcypromine and acetonitrile inhibited covalent binding of the 2,6-isomer to olfactory microsomes. Glutathione (GSH) appeared to play a protective role as a scavenger of a reactive intermediate whereas methyl-GSH did not alter covalent binding to olfactory microsomes. As determined by microautoradiography, binding of the 2,6-chlorinated isomer in the olfactory mucosa was confined to the Bowman's glands. Both isomers showed a low binding to liver microsomes and caused no liver injury. We suggest that a CYP2A-catalyzed activation of the 2,6-chlorinated dichlorophenyl methylsulphone to a reactive intermediate and adduct formation in the Bowman's glands will initiate a site-specific toxicity of this isomer in the olfactory mucosa.

Place, publisher, year, edition, pages
2003. Vol. 31, no 4, 364-372 p.
Keyword [en]
Bowman's gland, olfactory epithelium, 2, 6-dichlorophenyl methylsulphone, covalent binding, CYP2A, olfactory mucosa, rat, nasal toxicity
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-93786DOI: 10.1080/01926230390201075PubMedID: 12851101OAI: oai:DiVA.org:uu-93786DiVA: diva2:167375
Available from: 2005-11-25 Created: 2005-11-25 Last updated: 2017-12-14Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 23
Keyword
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
Identifiers
urn:nbn:se:uu:diva-6161 (URN)91-554-6408-4 (ISBN)
Public defence
2005-12-16, B41, BMC, Uppsala, 13:15
Opponent
Supervisors
Available from: 2005-11-25 Created: 2005-11-25Bibliographically approved
2. Neurotoxic Effects of Dichlorophenyl Methylsulphones Related to Olfactory Mucosal Lesions
Open this publication in new window or tab >>Neurotoxic Effects of Dichlorophenyl Methylsulphones Related to Olfactory Mucosal Lesions
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the highly potent olfactory mucosa toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) and its non-toxic 2,5-chlorinated isomer (2,5-diClPh-MeSO2). In mice, both substances bind firmly in the olfactory mucosa and the olfactory bulb, which are important components of the sensory system. The 2,6-isomer induces olfactory mucosal necrosis with permanent loss of olfactory neuroepithelium and olfactory nerves. A major objective was to clarify the cause of this isomer-specific toxicity, and to identify which physicochemical characteristics determine the olfactory toxicity. The neurobehavioural toxicity of these substances was also examined.

The results revealed a rapid CYP-catalysed covalent binding of 2,6-diClPh-MeSO2 in the rat olfactory mucosa, whereas the 2,5-dichlorinated isomer was not covalently bound.

Acute and chronic olfactory mucosal pathology were investigated and compared in rats and mice. Twenty-four hours after dosing to rats, 2,6-diClPh-MeSO2 induced Bowman’s glands necrosis and sloughing of the olfactory epithelium similar to that previously reported in mice. At 3 weeks, however, there were dramatic differences in histological lesions. In mice, large parts of olfactory epithelium were replaced by respiratory-like epithelium. Large, bilateral, fibrous, cartilage and bone containing polyps occluding the lumen were confirmed. In rats, only minor patches of olfactory epithelium were replaced by a metaplastic atypical respiratory-like epithelium. 2,5-diClPh-MeSO2 was non-toxic in rats as well as in mice.

In mice, 2,6-diClPh-MeSO2 induced a dose-dependent and long-lasting ( ≥12 weeks) hyperactivity as well as long-lasting maze learning deficits. At 2 weeks hyperactivity and maze learning deficits were observed also in rats. Unexpectedly, 2,5-diClPh-MeSO2 induced hyperactivity that lasted for two weeks. No effect on maze learning was observed with this isomer. No major differences between male and female rats or mice were found.

In conclusion, the results show that a CYP-catalysed formation and covalent binding of a reactive 2,6-diClPh-MeSO2-metabolite in the Bowman’s glands precede the high olfactory mucosal toxicity in rodents. As determined by QSAR-modelling, a 2,6-dichlorinated benzene derivative with a large, polar, and strong electron withdrawing substituent in the primary position has the potential of being an olfactory mucosal toxicant. The observed 2,6-diClPh-MeSO2-induced increase in motor activity, and maze learning deficits, were not correlated to the olfactory mucosal lesions. I propose that 2,6-diClPh-MeSO2 causes a direct effect in the brain leading to neurobehaviuoral deficits.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 53 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 858
Keyword
Biology, olfcatory toxicity, olfactory bulb, aryl methylsulphone, neurotoxicity, QSAR, Biologi
National Category
Biological Sciences
Research subject
Ecotoxicology
Identifiers
urn:nbn:se:uu:diva-3463 (URN)91-554-5668-5 (ISBN)
Public defence
2003-06-02, Lindahlsalen, EBC, Uppsala, 13:00
Opponent
Supervisors
Available from: 2003-05-12 Created: 2003-05-12 Last updated: 2013-07-02Bibliographically approved

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