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. 1990 Apr;85:177–186. doi: 10.1289/ehp.85-1568341

Biotransformation enzymes in the rodent nasal mucosa: the value of a histochemical approach.

M S Bogdanffy 1
PMCID: PMC1568341  PMID: 2200661

Abstract

An increasing number of chemicals have been identified as being toxic to the nasal mucosa of rats. While many chemicals exert their effects only after inhalation exposure, others are toxic following systemic administration, suggesting that factors other than direct deposition on the nasal mucosa may be important in mechanisms of nasal toxicity. The mucosal lining of the nasal cavity consists of a heterogeneous population of ciliated and nonciliated cells, secretory cells, sensory cells, and glandular and other cell types. For chemicals that are metabolized in the nasal mucosa, the balance between metabolic activation and detoxication within a cell type may be a key factor in determining whether that cell type will be a target for toxicity. Recent research in the area of xenobiotic metabolism in nasal mucosa has demonstrated the presence of many enzymes previously described in other tissues. In particular, carboxylesterase, aldehyde dehydrogenase, cytochromes P-450, epoxide hydrolase, and glutathione S-transferases have been localized by histochemical techniques. The distribution of these enzymes appears to be cell-type-specific and the presence of the enzyme may predispose particular cell types to enhanced susceptibility or resistance to chemical-induced injury. This paper reviews the distribution of these enzymes within the nasal mucosa in the context of their contribution to xenobiotic metabolism. The localization of the enzymes by histochemical techniques has provided important information on the potential mechanism of action of esters, aldehydes, and cytochrome P-450 substrates known to injure the nasal mucosa.

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Selected References

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  1. Appelman L. M., Woutersen R. A., Feron V. J. Inhalation toxicity of acetaldehyde in rats. I. Acute and subacute studies. Toxicology. 1982;23(4):293–307. doi: 10.1016/0300-483x(82)90068-3. [DOI] [PubMed] [Google Scholar]
  2. Baron J., Burke J. P., Guengerich F. P., Jakoby W. B., Voigt J. M. Sites for xenobiotic activation and detoxication within the respiratory tract: implications for chemically induced toxicity. Toxicol Appl Pharmacol. 1988 May;93(3):493–505. doi: 10.1016/0041-008x(88)90053-1. [DOI] [PubMed] [Google Scholar]
  3. Belinsky S. A., Walker V. E., Maronpot R. R., Swenberg J. A., Anderson M. W. Molecular dosimetry of DNA adduct formation and cell toxicity in rat nasal mucosa following exposure to the tobacco specific nitrosamine 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone and their relationship to induction of neoplasia. Cancer Res. 1987 Nov 15;47(22):6058–6065. [PubMed] [Google Scholar]
  4. Bogdanffy M. S., Randall H. W., Morgan K. T. Biochemical quantitation and histochemical localization of carboxylesterase in the nasal passages of the Fischer-344 rat and B6C3F1 mouse. Toxicol Appl Pharmacol. 1987 Apr;88(2):183–194. doi: 10.1016/0041-008x(87)90004-4. [DOI] [PubMed] [Google Scholar]
  5. Bogdanffy M. S., Randall H. W., Morgan K. T. Histochemical localization of aldehyde dehydrogenase in the respiratory tract of the Fischer-344 rat. Toxicol Appl Pharmacol. 1986 Mar 15;82(3):560–567. doi: 10.1016/0041-008x(86)90291-7. [DOI] [PubMed] [Google Scholar]
  6. Bond J. A., Harkema J. R., Russell V. I. Regional distribution of xenobiotic metabolizing enzymes in respiratory airways of dogs. Drug Metab Dispos. 1988 Jan-Feb;16(1):116–124. [PubMed] [Google Scholar]
  7. Bond J. A. Some biotransformation enzymes responsible for polycyclic aromatic hydrocarbon metabolism in rat nasal turbinates: effects on enzyme activities of in vitro modifiers and intraperitoneal and inhalation exposure of rats to inducing agents. Cancer Res. 1983 Oct;43(10):4805–4811. [PubMed] [Google Scholar]
  8. Boorman G. A., Brown R., Gupta B. N., Uraih L. C., Bucher J. R. Pathologic changes following acute methyl isocyanate inhalation and recovery in B6C3F1 mice. Toxicol Appl Pharmacol. 1987 Mar 15;87(3):446–456. doi: 10.1016/0041-008x(87)90250-x. [DOI] [PubMed] [Google Scholar]
  9. Brittebo E. B. Metabolic activation of phenacetin in rat nasal mucosa: dose-dependent binding to the glands of Bowman. Cancer Res. 1987 Mar 1;47(5):1449–1456. [PubMed] [Google Scholar]
  10. Casanova-Schmitz M., David R. M., Heck H. D. Oxidation of formaldehyde and acetaldehyde by NAD+-dependent dehydrogenases in rat nasal mucosal homogenates. Biochem Pharmacol. 1984 Apr 1;33(7):1137–1142. doi: 10.1016/0006-2952(84)90526-4. [DOI] [PubMed] [Google Scholar]
  11. Dahl A. R., Coslett D. S., Bond J. A., Hesseltine G. R. Metabolism of benzo[a]pyrene on the nasal mucosa of Syrian hamsters: comparison to metabolism by other extrahepatic tissues and possible role of nasally produced metabolites in carcinogenesis. J Natl Cancer Inst. 1985 Jul;75(1):135–139. [PubMed] [Google Scholar]
  12. Dahl A. R., Hadley W. M., Hahn F. F., Benson J. M., McClellan R. O. Cytochrome P-450-dependent monooxygenases in olfactory epithelium of dogs: possible role in tumorigenicity. Science. 1982 Apr 2;216(4541):57–59. doi: 10.1126/science.7063870. [DOI] [PubMed] [Google Scholar]
  13. Dahl A. R., Miller S. C., Petridou-Fischer J. Carboxylesterases in the respiratory tracts of rabbits, rats and Syrian hamsters. Toxicol Lett. 1987 Apr;36(2):129–136. doi: 10.1016/0378-4274(87)90176-7. [DOI] [PubMed] [Google Scholar]
  14. Ding X. X., Koop D. R., Crump B. L., Coon M. J. Immunochemical identification of cytochrome P-450 isozyme 3a (P-450ALC) in rabbit nasal and kidney microsomes and evidence for differential induction by alcohol. Mol Pharmacol. 1986 Oct;30(4):370–378. [PubMed] [Google Scholar]
  15. Foster J. R., Elcombe C. R., Boobis A. R., Davies D. S., Sesardic D., McQuade J., Robson R. T., Hayward C., Lock E. A. Immunocytochemical localization of cytochrome P-450 in hepatic and extra-hepatic tissues of the rat with a monoclonal antibody against cytochrome P-450 c. Biochem Pharmacol. 1986 Dec 15;35(24):4543–4554. doi: 10.1016/0006-2952(86)90777-x. [DOI] [PubMed] [Google Scholar]
  16. Hadley W. M., Dahl A. R. Cytochrome P-450 dependent monooxygenase activity in rat nasal epithelial membranes. Toxicol Lett. 1982 Mar;10(4):417–422. doi: 10.1016/0378-4274(82)90240-5. [DOI] [PubMed] [Google Scholar]
  17. Hadley W. M., Dahl A. R. Cytochrome P-450-dependent monooxygenase activity in nasal membranes of six species. Drug Metab Dispos. 1983 May-Jun;11(3):275–276. [PubMed] [Google Scholar]
  18. Hecht S. S., Chen C. B., Ohmori T., Hoffmann D. Comparative carcinogenicity in F344 rats of the tobacco-specific nitrosamines, N'-nitrosonornicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Res. 1980 Feb;40(2):298–302. [PubMed] [Google Scholar]
  19. Hurtt M. E., Thomas D. A., Working P. K., Monticello T. M., Morgan K. T. Degeneration and regeneration of the olfactory epithelium following inhalation exposure to methyl bromide: pathology, cell kinetics, and olfactory function. Toxicol Appl Pharmacol. 1988 Jun 30;94(2):311–328. doi: 10.1016/0041-008x(88)90273-6. [DOI] [PubMed] [Google Scholar]
  20. Isaka H., Yoshii H., Otsuji A., Koike M., Nagai Y., Koura M., Sugiyasu K., Kanabayashi T. Tumors of Sprague-Dawley rats induced by long-term feeding of phenacetin. Gan. 1979 Feb;70(1):29–36. [PubMed] [Google Scholar]
  21. Jeffery E. H., Haschek W. M. Protection by dimethylsulfoxide against acetaminophen-induced hepatic, but not respiratory toxicity in the mouse. Toxicol Appl Pharmacol. 1988 May;93(3):452–461. doi: 10.1016/0041-008x(88)90048-8. [DOI] [PubMed] [Google Scholar]
  22. Lee K. P., Trochimowicz H. J. Induction of nasal tumors in rats exposed to hexamethylphosphoramide by inhalation. J Natl Cancer Inst. 1982 Jan;68(1):157–171. [PubMed] [Google Scholar]
  23. Lindahl R., Evces S. Comparative subcellular distribution of aldehyde dehydrogenase in rat, mouse and rabbit liver. Biochem Pharmacol. 1984 Nov 1;33(21):3383–3389. doi: 10.1016/0006-2952(84)90109-6. [DOI] [PubMed] [Google Scholar]
  24. Longo V., Citti L., Gervasi P. G. Metabolism of diethylnitrosamine by nasal mucosa and hepatic microsomes from hamster and rat: species specificity of nasal mucosa. Carcinogenesis. 1986 Aug;7(8):1323–1328. doi: 10.1093/carcin/7.8.1323. [DOI] [PubMed] [Google Scholar]
  25. Löfberg B., Tjälve H. Autoradiography of [14C]N-nitrosodiethanolamine in Sprague-Dawley rats. Cancer Lett. 1985 Mar;26(2):129–137. doi: 10.1016/0304-3835(85)90018-7. [DOI] [PubMed] [Google Scholar]
  26. Miller R. R., Ayres J. A., Jersey G. C., McKenna M. J. Inhalation toxicity of acrylic acid. Fundam Appl Toxicol. 1981 May-Jun;1(3):271–277. doi: 10.1016/s0272-0590(81)80127-3. [DOI] [PubMed] [Google Scholar]
  27. Miller R. R., Hermann E. A., Young J. T., Calhoun L. L., Kastl P. E. Propylene glycol monomethyl ether acetate (PGMEA) metabolism, disposition, and short-term vapor inhalation toxicity studies. Toxicol Appl Pharmacol. 1984 Sep 30;75(3):521–530. doi: 10.1016/0041-008x(84)90188-1. [DOI] [PubMed] [Google Scholar]
  28. Miller R. R., Young J. T., Kociba R. J., Keyes D. G., Bodner K. M., Calhoun L. L., Ayres J. A. Chronic toxicity and oncogenicity bioassay of inhaled ethyl acrylate in Fischer 344 rats and B6C3F1 mice. Drug Chem Toxicol. 1985;8(1-2):1–42. doi: 10.3109/01480548509011632. [DOI] [PubMed] [Google Scholar]
  29. Monteiro-Riviere N. A., Popp J. A. Ultrastructural characterization of the nasal respiratory epithelium in the rat. Am J Anat. 1984 Jan;169(1):31–43. doi: 10.1002/aja.1001690103. [DOI] [PubMed] [Google Scholar]
  30. Randall H. W., Bogdanffy M. S., Morgan K. T. Enzyme histochemistry of the rat nasal mucosa embedded in cold glycol methacrylate. Am J Anat. 1987 May;179(1):10–17. doi: 10.1002/aja.1001790103. [DOI] [PubMed] [Google Scholar]
  31. Simmons P. A., Rafols J. A., Getchell T. V. Ultrastructural changes in olfactory receptor neurons following olfactory nerve section. J Comp Neurol. 1981 Apr 1;197(2):237–257. doi: 10.1002/cne.901970206. [DOI] [PubMed] [Google Scholar]
  32. Stinson S. F., Reznik G., Ward J. M. Characteristics of proliferative lesions in the nasal cavities of mice following chronic inhalation of 1,2-dibromoethane. Cancer Lett. 1981 Mar;12(1-2):121–129. doi: 10.1016/0304-3835(81)90047-1. [DOI] [PubMed] [Google Scholar]
  33. Stott W. T., McKenna M. J. Hydrolysis of several glycol ether acetates and acrylate esters by nasal mucosal carboxylesterase in vitro. Fundam Appl Toxicol. 1985 Apr;5(2):399–404. doi: 10.1016/0272-0590(85)90088-0. [DOI] [PubMed] [Google Scholar]
  34. Stott W. T., McKenna M. J. The comparative absorption and excretion of chemical vapors by the upper, lower, and intact respiratory tract of rats. Fundam Appl Toxicol. 1984 Aug;4(4):594–602. doi: 10.1016/0272-0590(84)90049-6. [DOI] [PubMed] [Google Scholar]
  35. Swenberg J. A., Kerns W. D., Mitchell R. I., Gralla E. J., Pavkov K. L. Induction of squamous cell carcinomas of the rat nasal cavity by inhalation exposure to formaldehyde vapor. Cancer Res. 1980 Sep;40(9):3398–3402. [PubMed] [Google Scholar]
  36. Thyssen J., Althoff J., Kimmerle G., Mohr U. Inhalation studies with benzo[a]pyrene in Syrian golden hamsters. J Natl Cancer Inst. 1981 Mar;66(3):575–577. [PubMed] [Google Scholar]
  37. Tjälve H., Castonguay A., Rivenson A. Microautoradiographic localization of bound metabolites in the nasal cavities of F344 rats treated with the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. J Natl Cancer Inst. 1985 Jan;74(1):185–189. [PubMed] [Google Scholar]
  38. Uraih L. C., Talley F. A., Mitsumori K., Gupta B. N., Bucher J. R., Boorman G. A. Ultrastructural changes in the nasal mucosa of Fischer 344 rats and B6C3F1 mice following an acute exposure to methyl isocyanate. Environ Health Perspect. 1987 Jun;72:77–88. doi: 10.1289/ehp.877277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Voigt J. M., Guengerich F. P., Baron J. Localization of a cytochrome P-450 isozyme (cytochrome P-450 PB-B) and NADPH-cytochrome P-450 reductase in rat nasal mucosa. Cancer Lett. 1985 Jul;27(3):241–247. doi: 10.1016/0304-3835(85)90180-6. [DOI] [PubMed] [Google Scholar]
  40. Wilmer J. W., Woutersen R. A., Appelman L. M., Leeman W. R., Feron V. J. Subacute (4-week) inhalation toxicity study of formaldehyde in male rats: 8-hour intermittent versus 8-hour continuous exposures. J Appl Toxicol. 1987 Feb;7(1):15–16. doi: 10.1002/jat.2550070104. [DOI] [PubMed] [Google Scholar]
  41. Woutersen R. A., Appelman L. M., Van Garderen-Hoetmer A., Feron V. J. Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. Toxicology. 1986 Oct;41(2):213–231. doi: 10.1016/0300-483x(86)90201-5. [DOI] [PubMed] [Google Scholar]
  42. Woutersen R. A., Appelman L. M., Wilmer J. W., Falke H. E., Feron V. J. Subchronic (13-week) inhalation toxicity study of formaldehyde in rats. J Appl Toxicol. 1987 Feb;7(1):43–49. doi: 10.1002/jat.2550070108. [DOI] [PubMed] [Google Scholar]

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