Cyp2a5-Mediated Activation and Early Ultrastructural Changes in the Olfactory Mucosa: Studies on 2,6-Dichlorophenyl Methylsulfone

Franzén, Anna; Carlsson, Carina; Hermansson, Veronica; Lang, Matti A.; Brittebo, Eva B.

doi:10.1124/dmd.105.006221

Cited by 11 publications

(6 citation statements)

References 32 publications

(56 reference statements)

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“…PYR did not enhance Cyp1a1/2- and Cyp2b9/10-mediated activities in any mouse strain (i.e., IFs were nearly 1), a finding that is consistent with the notion that this heterocyclic diazole compound is a selective inducer of Cyp2a, 2j and Cyp2e1 activities in the liver tissue [22]. …”

Section: Resultssupporting

confidence: 79%

“…Notwithstanding the marked variation of constitutive activities, mice from all strains evaluated in this study responded to challenges with PB and PYR, a finding that suggests that constitutive strain-related differences do not involve xenoreceptors or mechanisms by which Cyp2a5-mediated activity is induced by xenobiotics. It is of note that PB, a pleiotropic inducer of mice Cyp2a5, 2b9/10, 3a11 and other CYP isoforms, and PYR, an inducer of Cyp2a4, 2a5, 2e1 and 2j, enhance Cyp2a5-catalyzed activities by distinct mechanisms [20–22]. …”

Section: Resultsmentioning

confidence: 99%

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Interstrain differences in the expression and activity of Cyp2a5 in the mouse liver

et al. 2017

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BackgroundCytochrome P450 2A5 (Cyp2a5), a mouse enzyme orthologous of human CYP2A6, catalyzes a number of toxicologically important reactions, including the metabolism of nicotine, aflatoxin B1, and several other xeno- and endobiotics. Cyp2a5 expression is complex and not yet fully understood. We investigated inter-strain differences in the activity and mRNA expression of hepatic Cyp2a5. Cyp1a1/2 and Cyp2b9/10 activities were evaluated for comparative purposes. Data on the interstrain differences in the expression and activity of Cyp2a5 are important to select a suitable mouse model for studying CYP2A6-mediated metabolism.ResultsActivity of Cyp2a5 (coumarin 7-hydroxylase) was highest in DBA-2 and DBA-1, intermediate in B6D2F1 (hybrid) and low in the remaining strains (C57BL/6, C57BL/10, CBA, BALB/cAn, SW). Contrasting with the activity, background levels of Cyp2a4/5 mRNA did not differ between high- and low-activity murine strains. Phenobarbital (PB, 80 mg/kg body weight/day × 3 days, i.p.) increased Cyp2a5, Cyp1a1/2 (ethoxyresorufin-O-deethylase) and Cyp2b9/10 (bezyloxyresorufin-O-debenzylase) activities while only Cyp2a5 was enhanced by pyrazole (PYR, 100 mg/kg body weight/day × 3 days, i.p.). Inductions of Cyp2a5 activity by PYR and PB were accompanied by increases of Cyp2a4/5 mRNA. PYR and PB did not upregulate heme oxygenase-1 (hmox-1) mRNA expression in any strain, a finding that is apparently at odds with the notion that Cyp2a5 and hmox-1 inductions are coordinated events.ConclusionsSince background levels of Cyp2a4/5 gene transcripts of high-activity strains did not differ from those of low-activity mice, distinct constitutive activities did not result from different transcription rates and/or mRNA half-lives. Results therefore suggested that interstrain differences in constitutive activity of Cyp2a5 possibly arise from distinct translation efficiencies, protein half-lives and/or enzyme kinetics toward the substrate. Data from this study indicated that all tested strains are suitable models for studying toxicants that are substrates for human CYP2A6; DBA-2, DBA-1 and the hybrid B62DF1, however, have the advantage of presenting high constitutive activities of Cyp2a5.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-017-2435-x) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Interstrain differences in the expression and activity of Cyp2a5 in the mouse liver

et al. 2017

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“…Aryl methyl sulfones (Figure 4) are biotransformants formed from chloro aryl hydrocarbons derived from compounds such as 1,1,1-trichloro-2,2-bis( p -chlorophenyl)ethane (DDT) and polychlorinated biphenyls (PCBs) following conjugation with glutathione (GSH) and degradation via mercapturic acid derivatives. 2,6-dichlorophenyl methylsulfone, as a single ip dose, produced necrosis preferentially in the BG and neuroepithelium in the dorsomedial olfactory region (Franzén et al, 2003), probably mediated by CYP2A5 activation, one of the prominent CYPs in the mouse (Zhuo et al, 2004; Franzén et al, 2006). By contrast, only minor damage occurred at this site in rats dosed with the 2,5-chlorinated isomer.…”

Section: Rodent Nasal Cytotoxinsmentioning

confidence: 99%

“…2,6-dichlorophenyl methylsulfone, as a single ip dose, produced necrosis preferentially in the BG and neuroepithelium in the dorsomedial olfactory region , probably mediated by CYP2A5 activation, one of the prominent CYPs in the mouse Franzén et al, 2006). By contrast, only minor damage occurred at this site in rats dosed with the 2,5-chlorinated isomer.…”

Section: Introductionmentioning

confidence: 95%

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

2006

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Toxicity and carcinogenicity in the mucosa of the nasal passages in rodents has been produced by a variety of organic chemicals which are systemically distributed. In this review, 14 such chemicals or classes were identified that produced rodent nasal cytotoxicity, but not carcinogenicity, and 11 were identified that produced nasal carcinogenicity. Most chemicals that affect the nasal mucosa were either concentrated in that tissue or readily activated there, or both. All chemicals with effects in the nasal mucosa that were DNA-reactive, were also carcinogenic, if adequately tested. None of the rodent nasal cytotoxins has been identified as a human systemic nasal toxin. This may reflect the lesser biotransformation activity of human nasal mucosa compared to rodent and the much lower levels of human exposures. None of the rodent carcinogens lacking DNA reactivity has been identified as a nasal carcinogen or other cancer hazard to humans. Some DNA-reactive rodent carcinogens that affect the nasal mucosa, as well as other tissues, have been associated with cancer at various sites in humans, but not the nasal cavity. Thus, findings in only the rodent nasal mucosa do not necessarily predict either a toxic or carcinogenic hazard to that tissue in humans.

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“…Both compounds induce dose-dependent decreases in the levels of nonprotein sulfhydryl residues (mainly glutathione, GSH), as well as detachment of neuroepithelium and tissue damage in the lamina propria (Brittebo, 1995; Bergstrom et al, 2003). A notable difference, however, is that while MMZ induces cell death in the OE primarily through apoptosis (Sakamoto et al, 2007), which is associated with minimal inflammatory response, DCBN-induced cell death in the OE was accompanied by excessive nasal inflammation and necrosis (Brandt et al, 1990; Bergman et al, 2002; Franzén et al, 2006; Mancuso et al, 1997). Nevertheless, the precise mechanism of the differential effects of the two olfactory toxicants on ORN regeneration, including the role of nasal inflammation, and the involvement of olfactory stem cells, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of permanent loss of olfactory receptor neurons induced by the herbicide 2,6-dichlorobenzonitrile: Effects on stem cells and noninvolvement of acute induction of the inflammatory cytokine IL-6

Xie

Fang

Schnittke

et al. 2013

Toxicology and Applied Pharmacology

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We explored the mechanisms underlying the differential effects of two olfactory toxicants, the herbicide 2,6-dichlorobenzonitrile (DCBN) and the anti-thyroid drug methimazole (MMZ), on olfactory receptor neuron (ORN) regeneration in mouse olfactory epithelium (OE). DCBN, but not MMZ, induced inflammation-like pathological changes in OE, and DCBN increased interleukin IL-6 levels in nasal-wash fluid to much greater magnitude and duration than did MMZ. At 24 h after DCBN injection, the population of horizontal basal cells (HBCs; reserve, normally quiescent OE stem cells) lining the DMM became severely depleted as some of them detached from the basal lamina, and sloughed into the nasal cavity along with the globose basal cells (GBCs; heterogeneous population of stem and progenitor cells), neurons, and sustentacular cells of the neuroepithelium. In contrast, the layer of HBCs remained intact in MMZ-treated mice, as only the mature elements of the neuroepithelium were shed. Despite the respiratory metaplasia accompanying the greater severity of the DCBN lesion, residual HBCs that survived intoxication were activated by the injury and contributed to the metaplastic respiratory epithelium, as shown by tracing their descendants in a K5CreErT2∷fl(stop)TdTomato strain of mice in which recombination causes HBCs to express TdTomato in advance of the lesion. But, contrary to published observations with MMZ, the HBCs failed to form ORNs. A role for IL-6 in suppressing ORN regeneration in DCBN-treated mice was rejected by the failure of the anti-inflammatory drug dexamethasone to prevent the subsequent respiratory metaplasia in the DMM, suggesting that other factors lead to HBC neuro-incompetence.

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Cyp2a5-Mediated Activation and Early Ultrastructural Changes in the Olfactory Mucosa: Studies on 2,6-Dichlorophenyl Methylsulfone

Cited by 11 publications

References 32 publications

Interstrain differences in the expression and activity of Cyp2a5 in the mouse liver

Interstrain differences in the expression and activity of Cyp2a5 in the mouse liver

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

Mechanisms of permanent loss of olfactory receptor neurons induced by the herbicide 2,6-dichlorobenzonitrile: Effects on stem cells and noninvolvement of acute induction of the inflammatory cytokine IL-6

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