Cytochrome P-450 dependent monooxygenase activity in rat nasal epithelial membranes

Hadley, William M.; Dahl, Alan R.

doi:10.1016/0378-4274(82)90240-5

Cited by 99 publications

(41 citation statements)

References 5 publications

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“…The mice were housed five per cage, with 12 hour light : dark cycle, and maintained on Purina Rat Chow and water ad libitum from 1 week before treatment to the end of the experiment. A 4% solution of 3MI in corn oil was injected intraperitoneally in four mice per group at a dose of 400 mg 3MI/kg.…”

Section: Methodsmentioning

confidence: 99%

3-Methylindole-Induced Nasal Mucosal Damage in Mice

1987

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Abstract. 3-Methylindole (3MI) damages nasal olfactory epithelium in mice. Lesions were studied histologically from 30 minutes to 28 days after intraperitoneal injection of 400 mg 3MI/kg. Cellular swelling was apparent in olfactory epithelium by 6 hours after injection of 3M1, while respiratory epithelium was normal. Necrosis of olfactory epithelium and subepithelial glands was diffuse by 48 hours. Subsequent ulceration resulted in epithelial hyperplasia, squamous metaplasia, fibroplasia, and ossification. Partially occlusive intranasal fibrous and osseous tissue persisted through 28 days after 3MI injection.3-Methylindole (3MI), a ruminal metabolite of tryptophan, is a cause of acute bovine pulmonary edema and interstitial emphysema (ABPE).8 Experimentally, 3MI also induces pulmonary edema in ~h e e p ,~.~ rats,21 and mice.Io In small ruminant^,^ mice,10,24 and 3MI selectively damages nonciliated bronchiolar epithelial (Clara) cells. Olfactory epithelium in the nasal mucosa of mice is also selectively injured by 3MI.25 3-Methylindole is thought to be metabolized by mixed function oxidases (MFO).6J3J7-20 In the nasal cavity, olfactory epithelium is the major site of MFO activity in rats, mice, hamsters, guinea pigs, rabbits, and dogs.I2 In the present study, C57BL mice were chosen as an inbred strain with inducible MFO l 6 to facilitate further study of 3MI toxicosis. This paper describes 3MI-induced nasal mucosal damage in mice. Materials and MethodsA total of 65 C57BW6N 35-day-old male mice (Hilltop Lab Animals, Inc.) were divided into 13 groups. The mice were housed five per cage, with 12 hour light : dark cycle, and maintained on Purina Rat Chow and water ad libitum from 1 week before treatment to the end of the experiment. A 4% solution of 3MI in corn oil was injected intraperitoneally in four mice per group at a dose of 400 mg 3MI/kg. The fifth mouse in each group received a comparable volume of corn oil by the same route and served as a control.Mice were killed by cervical dislocation %, 1, 6, 12, and 24 hours, and 2,3,5,7, 10, 14,2 1, and 28 days after injection of 3MI. Tissues were fixed by perfusion of 5 to 6 ml of cacodylate-buffered 2% formaldehyde1 Yo glutaraldehyde via the right cardiac ventricle. The head was removed and the nasal cavity flushed with the same fixative through a 20-gauge cannula inserted 2-3 mm into the nasopharynx. The skin and mandibles were removed, and the head was immersed in fixative for at least 48 hours. To decalcify bone, the head was immersed in equal volumes of 20% sodium citrate and 50% formic acid for approximately 24 hours, then transferred to a saturated solution of sodium bicarbonate and washed in running tap water overnight to return pH to neutral. Frontal sections of the head through the plane of the first molar tooth were embedded in methacrylate. Sections cut at 2-3 bm were stained with hematoxlyin and eosin (HE) for light microscopy. ResultsWithin 30 minutes of 3MI injection, mice were lethargic with slowed respiratory rate. By 24 hours, mice were huddled and c...

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Section: Methodsmentioning

confidence: 99%

3-Methylindole-Induced Nasal Mucosal Damage in Mice

1987

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“…Species differences in the oxidation of cytochrome P-450 substrates by nasal tissue have been observed (41), and these are particularly evident when examining the metabolism of benzo(a)pyrene. The total metabolism of benzo(a)pyrene is approximately equivalent for maxilloturbinate (respiratory mucosa) or ethmoturbinate (olfactory mucosa) tissue in the Syrian hamster (40).…”

Section: Metabolism Of P-450 Substratesmentioning

confidence: 99%

“…The latter studies were of particular importance since they suggested that agents reaching the nasal mucosa through the systemic circulation may be metabolically activated within target cells. Prior to 1982 when the group at Lovelace Inhalation Toxicology Research Institute first demonstrated the susceptibility of the rat and dog nasal mucosa to N-demethylate, a variety of cytochrome P-450 substrates, no other work had highlighted the potential importance of this tissue as a site for extrahepatic xenobiotic metabolism (8,9).…”

Section: Introductionmentioning

confidence: 99%

Biotransformation Enzymes in the Rodent Nasal Mucosa: The Value of a Histochemical Approach

Bogdanffy¹

1990

Environmental Health Perspectives

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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 oftheir 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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“…and aminopyrine (6) in the nasal mucosa is catalyzed by members of the cytochromes P450 superfamily (4,(7)(8)(9). In contrast to hepatic cytochrome P450, nasal cytochrome P450 activity is not increased after exposure to inducers such as phenobarbital, 3-methylcholanthrene, and benzo[a]pyrene (lo), and olfactory P450 activity is more sensitive to inhibition by metyrapone and alpha-naphthoflavone (ll), suggesting that the nasal mucosa contains forms of cytochromes P450 that are distinct from those found in the liver.…”

Section: Introductionmentioning

confidence: 99%

Localization and induction of cytochrome P450 1A1 and aryl hydrocarbon hydroxylase activity in rat nasal mucosa.

Voigt

Guengerich²,

Baron³

1993

J Histochem Cytochem.

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Cytochrome P450 1A1 was localized immunohistochemically and benzo[a]pyrene hydroxylase activity was identified in situ by means of fluorescence histochemistry in the nasal mucosa of untreated, 3-methylcholanthrene-treated or Aroclor 1254-treated rats. Cytochrome P450 1A1 was localized predominantly within Bowman's glands, with considerably less staining occurring in the olfactory epithelium of untreated rats. Similarly, benzo[a]pyrene was hydroxylated to the greatest extent in Bowman's glands and, to a lesser extent, in olfactory epithelial cells. Pre-treatment of tissue sections of nasal mucosa with anti-P450 1A1 inhibited most of the benzo[a]pyrene hydroxylase activity present. Although 3-methylcholanthrene treatment did not affect either cytochrome P450 1A1 or hydroxylase activity in the nasal mucosa, a single intraperitoneal injection of Aroclor 1254 significantly increased anti-P450 1A1 binding in Bowman's glands and in the olfactory and respiratory epithelia, and dramatically enhanced benzo[a]pyrene hydroxylase activity in the epithelia and the subepithelial ducts and glands in both the olfactory and respiratory regions. In contrast to its effects on cytochrome P450 1A1, Aroclor 1254 produced a considerably greater induction of hydroxylase activity in the respiratory region, especially in the seromucous glands, than in the olfactory region. These results suggest that Aroclor 1254 treatment also induces other forms of cytochrome P450 in the respiratory region of the nasal mucosa.

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Cytochrome P-450 dependent monooxygenase activity in rat nasal epithelial membranes

Cited by 99 publications

References 5 publications

3-Methylindole-Induced Nasal Mucosal Damage in Mice

3-Methylindole-Induced Nasal Mucosal Damage in Mice

Biotransformation Enzymes in the Rodent Nasal Mucosa: The Value of a Histochemical Approach

Localization and induction of cytochrome P450 1A1 and aryl hydrocarbon hydroxylase activity in rat nasal mucosa.

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