Update on olfactory mucosal metabolic enzymes: Age‐related changes and <i>N</i>‐acetyltransferase activities

Genter, Mary Beth

doi:10.1002/jbt.20029

Cited by 13 publications

(5 citation statements)

References 32 publications

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“…N-acetyltransferase transcripts, specifically the N-acetyltransferase 1 enzyme, which is widely distributed in the body, is present in the RE and OE, as well as the BGs (Debiec-Rychter et al, 1996). In fact, activity in the OM of Long-Evans rats is markedly higher than in the liver (Genter, 2004). Other enzymes, such as epoxide hydrolase, are higher in rats when compared to other species such as mice (Green et al, 2001).…”

Section: Introductionmentioning

confidence: 90%

“…No report of an association of nasal tumors in humans has been made for exposure to either 2,6-DMA or lidocaine. This is in spite of theoretical concerns raised by the fact that lidocaine is used as a nasal spray for the treatment of migraine headaches, as well as a local anesthetic during nasal surgery (Genter, 2004). Smokers exhibit NM alterations and have increased risk of sinonasal squamous cell carcinoma (Feron et al, 2001).…”

Section: Rodent Nasal Carcinogensmentioning

confidence: 99%

“…The rodent NM possesses substantial chemical biotransformation capability (Hadley and Dahl, 1982;Dahl, 1985;Longo et al, 1988;Dahl and Hadley, 1991;Bereziat et al, 1995;Genter et al, 1995b;Thornton-Manning and Dahl, 1997;Genter, 2004), which may play a role in olfaction (Anholt, 1989;Nef et al, 1989;Carr et al, 1990). Species differ in their specific levels of biotransformation capability (Hadley and Dahl, 1983;Thornton-Manning and Dahl, 1997).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 90%

Section: Rodent Nasal Carcinogensmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

2006

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“…The supranuclear cytoplasm of sustentacular cells has abundant smooth endoplasmic reticulum and xenobiotic-metabolizing enzymes (e.g., cytochrome P-450, flavin-containing monooxygenases, N-acetyltransferases). The metabolism in these cells may be important in detoxification of inhaled xenobiotics and in the function of smell (Dahl and Hadley, 1991; Reed, 1993; Ding, 2003; Genter, 2004; Ling et al, 2004). Sustentacular cells are also thought to contribute to the regulation of the ionic composition of the overlying mucous layer which undoubtedly affects the chemical interactions between odors and their ORs.…”

Section: Nasal Structure and Functionmentioning

confidence: 99%

The Nose Revisited: A Brief Review of the Comparative Structure, Function, and Toxicologic Pathology of the Nasal Epithelium

2006

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The nose is a very complex organ with multiple functions that include not only olfaction, but also the conditioning (e.g., humidifying, warming, and filtering) of inhaled air. The nose is also a "scrubbing tower" that removes inhaled chemicals that may be harmful to the more sensitive tissues in the lower tracheobronchial airways and pulmonary parenchyma. Because the nasal airway may also be a prime target for many inhaled toxicants, it is important to understand the comparative aspects of nasal structure and function among laboratory animals commonly used in inhalation toxicology studies, and how nasal tissues and cells in these mammalian species may respond to inhaled toxicants. The surface epithelium lining the nasal passages is often the first tissue in the nose to be directly injured by inhaled toxicants. Five morphologically and functionally distinct epithelia line the mammalian nasal passages--olfactory, respiratory, squamous, transitional, and lymphoepithelial--and each nasal epithelium may be injured by an inhaled toxicant. Toxicant-induced epithelial lesions in the nasal passages of laboratory animals (and humans) are often site-specific and dependent on the intranasal regional dose of the inhaled chemical and the sensitivity of the nasal epithelial tissue to the specific chemical. In this brief review, we present examples of nonneoplastic epithelial lesions (e.g., cell death, hyperplasia, metaplasia) caused by single or repeated exposure to various inhaled chemical toxicants. In addition, we provide examples of how nasal maps may be used to record the character, magnitude and distribution of toxicant-induced epithelial injury in the nasal airways of laboratory animals. Intranasal mapping of nasal histopathology (or molecular and biochemical alterations to the nasal mucosa) may be used along with innovative dosimetric models to determine dose/response relationships and to understand if site-specific lesions are driven primarily by airflow, by tissue sensitivity, or by another mechanism of toxicity. The present review provides a brief overview of comparative nasal structure, function and toxicologic pathology of the mammalian nasal epithelium and a brief discussion on how data from animal toxicology studies have been used to estimate the risk of inhaled chemicals to human health.

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“…An alternative mutagenic mechanism is transformation of DEA to a nitrosobenzene derivative (Kimmel et al, 1986) possibly by N -hydroxylation followed by acetylation (Guengerich, 1992). Acetylation activity in olfactory mucosa has been shown to significantly exceed that of liver using 4 different substrates (Genter, 2004). Recent work suggests that CYP2A3 is involved in the bioactivation of DEA, as the distribution of this enzyme in olfactory tissues from control rats correlates highly with the ultimate pattern of tumor formation in alachlor-treated animals (Genter et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Reduction of Alachlor-Induced Olfactory Mucosal Neoplasms by the Matrix Metalloproteinase Inhibitor Ro 28-2653

et al. 2005

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Chronic exposure to the chloracetanilide herbicide alachlor has been shown to cause olfactory mucosal neoplasms. Genomic analysis of olfactory mucosa from rats given alachlor (126 mg/kg/d) for from 1 day to 18 mo suggested that matrix metalloproteinases MMP-2 and MMP-9 were upregulated in the month following initiation of treatment. The present studies were designed to confirm this latter finding and to explore the potential role of MMPs in alachlor-induced olfactory carcinogenesis. Zymographic analysis of olfactory mucosal extracts confirmed that MMP-2 activity is higher in the olfactory mucosa of alachlor-treated rats. Therefore, rats were fed alachlor (126 mg/kg/d in the diet for 1 year) either with or without the MMP-2/MMP-9 inhibitor Ro 28-2653 (100 mg/kg daily by gavage for the first 2 months of alachlor treatment). The number of olfactory mucosal neoplasms was reduced by 25% after 1 year of alachlor treatment in rats that received both alachlor and Ro 28-2653. The morphology of alachlor-induced olfactory tumors was similar whether or not Ro 28-2653 had been given; the MMP inhibitor itself had no impact on olfactory mucosal histology. These data confirm that olfactory mucosal MMP-2 activity is increased following short-term alachlor exposure and show that administration of an MMP-2/9 inhibitor reduced the incidence of olfactory neoplasms in alachlor-treated rats, thereby implicating MMP-2 activity as a mediator of alachlor-induced carcinogenicity.

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Update on olfactory mucosal metabolic enzymes: Age‐related changes and N‐acetyltransferase activities

Cited by 13 publications

References 32 publications

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

The Nose Revisited: A Brief Review of the Comparative Structure, Function, and Toxicologic Pathology of the Nasal Epithelium

Reduction of Alachlor-Induced Olfactory Mucosal Neoplasms by the Matrix Metalloproteinase Inhibitor Ro 28-2653

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