Critical factors in assessing risk from exposure to nasal carcinogens

Bogdanffy, Matthew S.; Mathison, Brian H.; Kuykendall, Jim R.; Harman, Anne E

doi:10.1016/s0027-5107(97)00131-0

Cited by 18 publications

(12 citation statements)

References 46 publications

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“…For example, the relative proportions of the nasal cavity occupied by respiratory and olfactory mucosa is very different in rodents vs. humans. Respiratory and olfactory mucosa each occupy approximately 50% of the surface of the rat nasal cavity, while in the human nose, <10% of the surface is covered by olfactory mucosa, with respiratory mucosa covering the remainder (24)(25)(26). There may also be differences in the metabolic enzyme content between rodent and human nasal tissues; however it is known that both rats and humans express the pi form of glutathione S-transferase (27).…”

Section: Hplc Analysismentioning

confidence: 99%

Characterization of lidocaine metabolism by rat nasal microsomes: implications for nasal drug delivery

Deshpande

Genter

Jung

et al. 1999

Eur. J. Drug Metab. Pharmacokinet.

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Lidocaine has been recently approved for use as an intranasal spray in the treatment of migraine. In this study, we investigated the metabolism of lidocaine to its primary metabolite monoethylglycine xylidide (MEGX), by rat nasal olfactory and respiratory microsomes. The metabolic parameters were compared with metabolism employing rat and human hepatic microsomes. The olfactory and respiratory microsomes both exhibited considerable activity for conversion of lidocaine to MEGX in comparison with the activity in the hepatic tissues. The rat olfactory microsomes had a markedly higher affinity than the rat hepatic or respiratory microsomes. However, the turnover rate was only about one-half that of rat liver. Employing Western immunoblotting we investigated the presence of cytochrome P450s (CYPs) 1A2, 3A2, 2B1 and 2C11 in rat nasal tissues; these isozymes are known to partcipated in the metabolism of lidocaine in rat liver. These isozymes were found to be present in significant amounts in both the nasal olfactory and respiratory tissue; this is the first known report of the presence of CYP2C11 in nasal mucosae. Our studies underscore the importance of CYP-mediated drug metabolism in nasal tissues. The effect of this 'nasal first-pass' should be weighed carefully while considering the fate and the bioavailability of drugs delivered via the intranasal route.

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Section: Hplc Analysismentioning

confidence: 99%

Characterization of lidocaine metabolism by rat nasal microsomes: implications for nasal drug delivery

Deshpande

Genter

Jung

et al. 1999

Eur. J. Drug Metab. Pharmacokinet.

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“…Up through 1997, excellent reviews of xenobiotic effects in rodent nasal mucosa (NM) were provided by several investigators (Dahl and Hadley, 1991; Brittebo, 1997; Monticello and Morgan, 1997; Schuller, 1997). The need for an understanding of carcinogenic susceptibility factors in rodent and human nasal tissues in order to develop plausible modes of action has been highlighted (Bogdanffy et al, 1997). The purpose of this review is to expand on these earlier reports with new information on this topic directed to evaluation of human risk from systemic exposure to rodent nasal cytotoxins and carcinogens.…”

Section: Introductionmentioning

confidence: 99%

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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“…As the first site of contact of the respiratory tract with the environment, it is a common site for absorption of many gases and vapors and for particle deposition-a prime site for toxicant-induced pathology (14,15). Human nasal neoplasms may be related to exposure to environmental factors, including tobacco smoke, dust, metals, aldehydes, chemicals, and viruses (16,17). Oxidative DNA damage is generally regarded as a significant contributory cause of cancer for some environmental pollutants (18).…”

mentioning

confidence: 99%

8-hydroxy-2'-deoxyguanosine, a major mutagenic oxidative DNA lesion, and DNA strand breaks in nasal respiratory epithelium of children exposed to urban pollution.

Calderón‐Garcidueñas

Wen-Wang

Zhang

et al. 1999

Environ Health Perspect

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Southwest metropolitan Mexico City children are repeatedly exposed to high levels of a complex mixture of air pollutants, including ozone, particulate matter, aldehydes, metals, and nitrogen oxides. We explored nasal cell 8-hydroxy-2'-deoxyguanosine (8-OHdG), a major mutagenic lesion producing G-->T transversion mutations, using an immunohistochemical method, and DNA single strand breaks (ssb) using the single cell gel electrophoresis assay as biomarkers of oxidant exposure. Nasal biopsies from the posterior inferior turbinate were examined in children in grades one through five, including 12 controls from a low-polluted coastal town and 87 Mexico City children. Each biopsy was divided for the 8-OHdG and DNA ssb assays. There was an age-dependent increase in the percentage of nasal cells with DNA tails > 10 microm in Mexico City children: 19 +/- 9% for control cells, and 43 +/- 4, 50 +/- 16, 56 +/- 17, 60 +/- 17 and 73 +/- 14%, respectively, for first through fifth graders (p < 0.05). Nasal ssb were significantly higher in fifth graders than in first graders (p < 0.05). Higher levels (2.3- to 3-fold) of specific nuclear staining for 8-OHdG were observed in exposed children as compared to controls (p < 0.05). These results suggest that DNA damage is present in nasal epithelial cells in Mexico City children. Persistent oxidative DNA damage may ultimately result in a selective growth of pr eneoplastic nasal initiated cells in this population and the potential for nasal neoplasms may increase with age. The combination of 8-OHdG and DNA ssb should be useful for monitoring oxidative damage in people exposed to polluted atmospheres.

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Critical factors in assessing risk from exposure to nasal carcinogens

Cited by 18 publications

References 46 publications

Characterization of lidocaine metabolism by rat nasal microsomes: implications for nasal drug delivery

Characterization of lidocaine metabolism by rat nasal microsomes: implications for nasal drug delivery

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

8-hydroxy-2'-deoxyguanosine, a major mutagenic oxidative DNA lesion, and DNA strand breaks in nasal respiratory epithelium of children exposed to urban pollution.

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