CYP2A5-mediated activation and early ultrastructural changes in the olfactory: Studies on 2,6-dichlorophenyl methylsulfone

Franzen, Anna, Carlsson, Carina, Hermansson, Veronica, Lang, Matti A. and Brittebo, Eva B. (2006). CYP2A5-mediated activation and early ultrastructural changes in the olfactory: Studies on 2,6-dichlorophenyl methylsulfone. In: , Drug Metabolism and Disposition: Proceedings of: International Society of the Study of Xenobiotics (ISSX) Meeting. International Society of the Study of Xenobiotics (ISSX) Meeting, Vancouver, Canada, (61-68). 29 Aug - 2 Sep 2004.


Author Franzen, Anna
Carlsson, Carina
Hermansson, Veronica
Lang, Matti A.
Brittebo, Eva B.
Title of paper CYP2A5-mediated activation and early ultrastructural changes in the olfactory: Studies on 2,6-dichlorophenyl methylsulfone
Conference name International Society of the Study of Xenobiotics (ISSX) Meeting
Conference location Vancouver, Canada
Conference dates 29 Aug - 2 Sep 2004
Proceedings title Drug Metabolism and Disposition: Proceedings of: International Society of the Study of Xenobiotics (ISSX) Meeting   Check publisher's open access policy
Journal name Drug Metabolism and Disposition   Check publisher's open access policy
Place of Publication Bethesda, USA
Publisher American Society for Pharmacology and Experimental Therapeutics
Publication Year 2006
Sub-type Fully published paper
DOI 10.1124/dmd.105.006221
ISSN 0090-9556
Volume 34
Issue 1
Start page 61
End page 68
Total pages 7
Language eng
Abstract/Summary 2,6-Dichlorophenyl methylsulfone (2,6-diClPh-MeSO2) is a potent olfactory toxicant reported to induce endoplasmic reticulum (ER) stress, caspase activation, and extensive cell death in mice. The aim of the present study was to examine cytochrome P450 (P450)- dependent bioactivation, nonprotein sulfhydryl (NP-SH) levels, and early ultrastructural changes in mouse olfactory mucosa following an i.p. injection of 2,6-diClPh-MeSO2 (32 mg/kg). A high covalent binding of 2,6-diClPh-14C-MeSO2 in olfactory mucosa S9 fraction was observed, and the CYP2A5/CYP2G1 substrates coumarin and dichlobenil significantly decreased the binding, whereas the CYP2E1 substrate chlorzoxazone had no effects. An increased bioactivation was detected in liver microsomes of mice pretreated with pyrazole, known to induce CYP2A4, 2A5, 2E1, and 2J, and addition of chlorzoxazone reduced this binding. 2,6-DiClPh-14CMeSO2 showed a marked covalent binding to microsomes of recombinant yeast cells expressing mouse CYP2A5 or human CYP2A6 compared with wild type. One and 4 h after a single injection of 2,6-diClPh-MeSO2, the NP-SH levels in the olfactory mucosa were significantly reduced compared with control, whereas there was no change in the liver. Ultrastructural studies revealed that ER, mitochondria, and secretory granules in nonneuronal cells were early targets 1 h after injection. We propose that lesions induced by 2,6-diClPh-MeSO2 in the mouse olfactory mucosa were initiated by a P450-mediated bioactivation in the Bowman’s glands and depletion of NP-SH levels, leading to disruption of ion homeostasis, organelle swelling, and cell death. The high expression of CYP2A5 in the olfactory mucosa is suggested to play a key role for the tissue-specific toxicity induced by 2,6- diClPh-MeSO2.
Subjects 11 Medical and Health Sciences
Keyword Coumarin 7-hydroxylase
Xenobiotic metabolism
Nasal cavity
Toxicity
Mice
Tissue
Expression
Induction
CYP2A5
Liver
Q-Index Code E1
Additional Notes Preliminary results presented at the Microsomes and Drug Oxidation (MDO) Meeting in Mainz, Germany, July 4–9, 2004, and at the International Society of the Study of Xenobiotics (ISSX) Meeting in Vancouver, Canada, Aug 29–Sept 2, 2004. Article, publication date, and citation information can be found at the links below.

 
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