Nasal Cavity Enzymes Involved in Xenobiotic Metabolism: Effects on the Toxicity of Inhalants

Dahl, Alan R.; Hadley, William M.

doi:10.3109/10408449109019571

Cited by 153 publications

(77 citation statements)

References 115 publications

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“…These enzymes may also protect the central nervous system against inhaled toxicants. P450 enzymes are, however, also central for the metabolic activation of foreign compounds into reactive, toxic metabolites, and olfactory P450s have been suggested to play a key role in the tissue-selective toxicity of drugs and chemicals in this tissue (Gaskell, 1990;Dahl and Hadley, 1991;Reed, 1993;Brittebo, 1997;Ding and Kaminsky, 2003). A decreased olfactory toxicity has been demonstrated after pretreatment with various P450 inhibitors (Brandt et al, 1990;Genter et al, 1994;Bahrami et al, 2000b).…”

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confidence: 91%

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

Franzén

Carlsson²,

Hermansson³

et al. 2005

Drug Metab Dispos

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ABSTRACT:2,6-Dichlorophenyl methylsulfone (2,6-diClPh-MeSO 2 ) 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-MeSO 2 (32 mg/kg). A high covalent binding of 2,6-diClPh-14 C-MeSO 2 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-14 CMeSO 2 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-MeSO 2 , 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-MeSO 2 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-MeSO 2 .The olfactory mucosa harbors a wide variety of xenobiotic-metabolizing enzymes including several cytochrome P450 (P450) forms; the most predominant are CYP2A3/5/10/13 and CYP2G1 (Ding and Kaminsky, 2003;Piras et al., 2003;Ling et al., 2004). The P450-mediated metabolism is generally regarded as a protection mechanism, and the high expression of drug-metabolizing P450s is most likely related to the clearance of odorants and other airborne chemicals. These enzymes may also protect the central nervous system against inhaled toxicants. P450 enzymes are, however, also central for the metabolic activation of foreign compounds into reactive, toxic metabolites, and olfactory P450s have been suggested to play a key role in the tissue-selective toxicity of drugs and chemicals in this tissue (Gaskell, 1990;Dahl and Hadley, 1991;Reed, 1993;Brittebo, 1997;Ding and Kaminsky, 2003). A decreased olfactory toxicity has been demonstrated after pretreatment with various P450 inhibitors (Brandt et al., 1990;Genter et al., 1994;Bahrami et al., 2000b). Many olfactory toxicants and carcinogens, including dichlobenil, coumarin, hexamethylphosphoramide, and the tobacco-specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are preferentially bioactivated to reactive interme...

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confidence: 91%

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

Franzén

Carlsson²,

Hermansson³

et al. 2005

Drug Metab Dispos

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“…2). The slow increase in lateral activity could be caused by the products of nasal chemical reactions catalyzed by various enzymes (21). Previous research has shown that the chemical reactions in the nasal cavities are capable of breaking down the odor molecules into smaller molecules (22).…”

Section: Modification Of Saps With Prolonged Exposurementioning

confidence: 99%

Assessment and discrimination of odor stimuli in rat olfactory bulb by dynamic functional MRI

Kida²,

Hyder³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

114

118

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Dynamic blood oxygenation level-dependent functional MRI was applied at 7 T in the rat olfactory bulb (OB) with pulsed delivery of iso-amyl acetate (IAA) and limonene. Acquisition times for singleslice and whole OB data were 8 and 32 s, respectively, with spatial resolution of 220 ؋ 220 ؋ 250 m. On an intrasubject basis, short IAA exposures of 0.6 min separated by 3.5-min intervals induced reproducible spatial activity patterns (SAPs) in the olfactory nerve layer, glomerular layer, and external plexiform layer. During long exposures (Ϸ10 min), the initially dominant dorsal SAPs declined in intensity and area, whereas in some OB regions, the initially weak ventral͞lateral SAPs increased first and then decreased. The SAPs of different concentrations were topologically similar, which implies that whereas an odor at various concentrations activates the same subsets of receptor cells, different concentrations are assessed and discriminated by variable magnitudes of laminarspecific activations. IAA and limonene reproducibly activated different subsets of receptor cells with some overlaps. Whereas qualitative topographical agreement was observed with results from other methods, the current dynamic blood oxygenation level-dependent functional MRI results can provide quantitative SAPs of the entire OB.blood oxygenation level-dependent ͉ functional mapping ͉ olfactory bulb I n mammals, olfactory behaviors such as determination of food palatability and searching require accurate assessment and discrimination of different odor types, concentrations, and exposure duration (1). Distinctions between these behavioral tasks are believed to rely on a spatial-encoding mechanism in which different odor and concentrations evoke spatial activity patterns (SAPs) in the olfactory bulb (OB). The SAPs are derived from functionally induced activity in olfactory receptor neurons that synapse at specific glomeruli (2).Insights into the coding of olfactory information have been partially inferred from SAPs in the OB, where the data can be obtained by various methods: 2-deoxyglucose autoradiography (3), electrophysiology (4), c-fos expression (5), functional MRI (fMRI) (6), and optical imaging of voltage-sensitive dyes (7) or intrinsic signals (8). Experimental limitations of each method affect data interpretations because each method maps a specific signal. Certain experimental criteria have to be met for olfactory perception to be systematically and ideally derived from the functional architecture revealed by the SAPs: (i) the neuroanatomy of the whole OB has to be mapped; (ii) the dynamic nature of SAPs in the whole OB has to be mapped with both high spatial and temporal resolutions; (iii) laminar-specific activations in the different layers have to be quantitated; and (iv) reproducibility of SAPs has to be established in a quantitative manner such that the effects of stimulus parameters (e.g., odor type, concentration, and exposure duration) can be easily identified and separated. If each criterion is met on an intrasubject basis by a par...

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“…The nasal tissues, both olfactory and respiratory, contain high amounts of numerous enzymes capable of metabolizing inhaled vapors (for a review see Dahl and Hadley, 1991). Among those enzymes, oxidoreductases, carboxylesterases, and cytochrome P-450 are likely to metabolize many of the VOCs shown in Table 2.…”

Section: Resultsmentioning

confidence: 99%

An Analysis of Nasal Irritation Thresholds Using a New Solvation Equation

Abraham

1996

Fundamental and Applied Toxicology

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In the present paper we have developed a quantitative structure-activity relationship (QSAR) equation for nasal pungency caused by nonreactive volatile organic compounds (VOCs).Our QSAR was developed upon previously published nasal pungency thresholds in anosmics, i.e., patients lacking a sense of smell and thus responding only to sensory irritation evoked by trigeminal nerve stimulation. The reported solvation equation, which fits the data with considerable precision, describes sensory potency in terms of interaction via electron pairs, dipolarity/polarizability, hydrogen bond acidity and basicity, and hydrophobicity. It correspondingly suggests relevant physicochemical properties of the biophase where the sensory response is brought about. The equation implies that in the range of molecular size where nonreactive VOCs can produce any pungency, transport from the air to the biophase strictly determines potency. In this respect, the potency of nasal pungency shares characteristics with the ability of VOCs to cause narcosis and anesthesia.

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Nasal Cavity Enzymes Involved in Xenobiotic Metabolism: Effects on the Toxicity of Inhalants

Cited by 153 publications

References 115 publications

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

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

Assessment and discrimination of odor stimuli in rat olfactory bulb by dynamic functional MRI

An Analysis of Nasal Irritation Thresholds Using a New Solvation Equation

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