CYP2A5-mediated activation and early ultrastructural changes in the olfactory mucosa: studies on 2,6-dichlorophenyl methylsulfone.
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-14C-MeSO2 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.
Franzén
Anna
A
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Carlsson
Carina
C
Hermansson
Veronica
V
Lang
Matti
M
Brittebo
Eva B
EB
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001555:Benzene Derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D002753:Chlorzoxazone / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D007274:Injections, Intraperitoneal; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011720:Pyrazoles / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*
C507859:2,6-dichlorophenyl methylsulfone; D001555:Benzene Derivatives; D003374:Coumarins; D009570:Nitriles; D011720:Pyrazoles; D013438:Sulfhydryl Compounds; D013450:Sulfones; C031280:pyrazole; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D002753:Chlorzoxazone; C055869:dichlobanil; D008797:Metyrapone