Relationship of cytochrome P450 activity to Clara cell cytotoxicity. II. Comparison of stereoselectivity of naphthalene epoxidation in lung and nasal mucosa of mouse, hamster, rat and rhesus monkey

Alan R Buckpitt, M. Buonarati, L. B. Avey, Min Chang Ai Min Chang, D. Morin, Charles Plopper

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Abstract

Naphthalene, a murine Clara cell cytotoxicant, is metabolized by cytochrome P450 monooxygenases to unstable, chiral epoxide metabolites which can conjugate with glutathione in the presence of glutathione transferases. Analysis of the three diasteriomeric glutathione adducts produced from conjugation of naphthalene oxides was used in these studies to characterize the stereo-chemistry of naphthalene epoxidation in preparations of nasal mucosa, lung and liver of the mouse, rat, hamster and monkey. The highest rates of naphthalene metabolism were observed in mouse lung and liver microsomal incubations. Rat, hamster and monkey lung microsomal preparations metabolized naphthalene at 12, 37, and 1%, respectively, of the rate observed in mouse lung. The ratio of chiral epoxides produced in microsomal incubations was dependent upon the concentration of naphthalene. At high substrate concentrations (0.25-1.0 mM), the ratio of 1R,2S- to 1S,2R- naphthalene oxide, as assessed by the glutathione adducts generated (adduct 2/adducts 1 + 3), in murine lung microsomal incubations was 10:1 and at low concentrations (0.062 mM and below) varied from 13.8:1 to 30:1. In contrast, the ratio of 1R,2S- to 1S,2R-naphthalene oxide produced in murine liver microsomes varied from 1:1 at high substrate concentrations to 5:1 at low substrate concentrations. The ratio of naphthalene oxides was unaffected by the concentration of glutathione in the incubation. In contrast to the preferential formation of 1R,2S-naphthalene oxide observed in mouse lung microsomal preparations, lung microsomes derived from the rat, hamster and monkey yielded 1R,2S- to 1S,2R-epoxide ratios of 0.48, 0.61 and 0.12, respectively, at 0.5 mM naphthalene. Substantial differences in the stereochemistry of naphthalene epoxidation also were noted in incubations of postmitochondrial supernatant from different regions of the nasal mucosa in the mouse, rat and hamster. The olfactory region showed the highest rates of substrate turnover and 1R,2S-naphthalene oxide was the predominant enantiomer formed in preparations from all three species. These studies show a good correlation between the rate and stereochemistry of naphthalene epoxidation with the species, tissue and regional toxicity of naphthalene in the rodent and suggest that primate airways may not be susceptible to naphthalene injury.

Original languageEnglish (US)
Pages (from-to)364-372
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume261
Issue number1
StatePublished - 1992

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Nasal Mucosa
Macaca mulatta
Cricetinae
Cytochrome P-450 Enzyme System
Lung
Glutathione
Epoxy Compounds
Haplorhini
naphthalene
Liver
Liver Microsomes
Microsomes
Mixed Function Oxygenases
Glutathione Transferase
Primates
naphthalene 1,2-oxide
Rodentia

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{a6762e039f054549a7e4e26e823e48ee,
title = "Relationship of cytochrome P450 activity to Clara cell cytotoxicity. II. Comparison of stereoselectivity of naphthalene epoxidation in lung and nasal mucosa of mouse, hamster, rat and rhesus monkey",
abstract = "Naphthalene, a murine Clara cell cytotoxicant, is metabolized by cytochrome P450 monooxygenases to unstable, chiral epoxide metabolites which can conjugate with glutathione in the presence of glutathione transferases. Analysis of the three diasteriomeric glutathione adducts produced from conjugation of naphthalene oxides was used in these studies to characterize the stereo-chemistry of naphthalene epoxidation in preparations of nasal mucosa, lung and liver of the mouse, rat, hamster and monkey. The highest rates of naphthalene metabolism were observed in mouse lung and liver microsomal incubations. Rat, hamster and monkey lung microsomal preparations metabolized naphthalene at 12, 37, and 1{\%}, respectively, of the rate observed in mouse lung. The ratio of chiral epoxides produced in microsomal incubations was dependent upon the concentration of naphthalene. At high substrate concentrations (0.25-1.0 mM), the ratio of 1R,2S- to 1S,2R- naphthalene oxide, as assessed by the glutathione adducts generated (adduct 2/adducts 1 + 3), in murine lung microsomal incubations was 10:1 and at low concentrations (0.062 mM and below) varied from 13.8:1 to 30:1. In contrast, the ratio of 1R,2S- to 1S,2R-naphthalene oxide produced in murine liver microsomes varied from 1:1 at high substrate concentrations to 5:1 at low substrate concentrations. The ratio of naphthalene oxides was unaffected by the concentration of glutathione in the incubation. In contrast to the preferential formation of 1R,2S-naphthalene oxide observed in mouse lung microsomal preparations, lung microsomes derived from the rat, hamster and monkey yielded 1R,2S- to 1S,2R-epoxide ratios of 0.48, 0.61 and 0.12, respectively, at 0.5 mM naphthalene. Substantial differences in the stereochemistry of naphthalene epoxidation also were noted in incubations of postmitochondrial supernatant from different regions of the nasal mucosa in the mouse, rat and hamster. The olfactory region showed the highest rates of substrate turnover and 1R,2S-naphthalene oxide was the predominant enantiomer formed in preparations from all three species. These studies show a good correlation between the rate and stereochemistry of naphthalene epoxidation with the species, tissue and regional toxicity of naphthalene in the rodent and suggest that primate airways may not be susceptible to naphthalene injury.",
author = "Buckpitt, {Alan R} and M. Buonarati and Avey, {L. B.} and {Ai Min Chang}, {Min Chang} and D. Morin and Charles Plopper",
year = "1992",
language = "English (US)",
volume = "261",
pages = "364--372",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Relationship of cytochrome P450 activity to Clara cell cytotoxicity. II. Comparison of stereoselectivity of naphthalene epoxidation in lung and nasal mucosa of mouse, hamster, rat and rhesus monkey

AU - Buckpitt, Alan R

AU - Buonarati, M.

AU - Avey, L. B.

AU - Ai Min Chang, Min Chang

AU - Morin, D.

AU - Plopper, Charles

PY - 1992

Y1 - 1992

N2 - Naphthalene, a murine Clara cell cytotoxicant, is metabolized by cytochrome P450 monooxygenases to unstable, chiral epoxide metabolites which can conjugate with glutathione in the presence of glutathione transferases. Analysis of the three diasteriomeric glutathione adducts produced from conjugation of naphthalene oxides was used in these studies to characterize the stereo-chemistry of naphthalene epoxidation in preparations of nasal mucosa, lung and liver of the mouse, rat, hamster and monkey. The highest rates of naphthalene metabolism were observed in mouse lung and liver microsomal incubations. Rat, hamster and monkey lung microsomal preparations metabolized naphthalene at 12, 37, and 1%, respectively, of the rate observed in mouse lung. The ratio of chiral epoxides produced in microsomal incubations was dependent upon the concentration of naphthalene. At high substrate concentrations (0.25-1.0 mM), the ratio of 1R,2S- to 1S,2R- naphthalene oxide, as assessed by the glutathione adducts generated (adduct 2/adducts 1 + 3), in murine lung microsomal incubations was 10:1 and at low concentrations (0.062 mM and below) varied from 13.8:1 to 30:1. In contrast, the ratio of 1R,2S- to 1S,2R-naphthalene oxide produced in murine liver microsomes varied from 1:1 at high substrate concentrations to 5:1 at low substrate concentrations. The ratio of naphthalene oxides was unaffected by the concentration of glutathione in the incubation. In contrast to the preferential formation of 1R,2S-naphthalene oxide observed in mouse lung microsomal preparations, lung microsomes derived from the rat, hamster and monkey yielded 1R,2S- to 1S,2R-epoxide ratios of 0.48, 0.61 and 0.12, respectively, at 0.5 mM naphthalene. Substantial differences in the stereochemistry of naphthalene epoxidation also were noted in incubations of postmitochondrial supernatant from different regions of the nasal mucosa in the mouse, rat and hamster. The olfactory region showed the highest rates of substrate turnover and 1R,2S-naphthalene oxide was the predominant enantiomer formed in preparations from all three species. These studies show a good correlation between the rate and stereochemistry of naphthalene epoxidation with the species, tissue and regional toxicity of naphthalene in the rodent and suggest that primate airways may not be susceptible to naphthalene injury.

AB - Naphthalene, a murine Clara cell cytotoxicant, is metabolized by cytochrome P450 monooxygenases to unstable, chiral epoxide metabolites which can conjugate with glutathione in the presence of glutathione transferases. Analysis of the three diasteriomeric glutathione adducts produced from conjugation of naphthalene oxides was used in these studies to characterize the stereo-chemistry of naphthalene epoxidation in preparations of nasal mucosa, lung and liver of the mouse, rat, hamster and monkey. The highest rates of naphthalene metabolism were observed in mouse lung and liver microsomal incubations. Rat, hamster and monkey lung microsomal preparations metabolized naphthalene at 12, 37, and 1%, respectively, of the rate observed in mouse lung. The ratio of chiral epoxides produced in microsomal incubations was dependent upon the concentration of naphthalene. At high substrate concentrations (0.25-1.0 mM), the ratio of 1R,2S- to 1S,2R- naphthalene oxide, as assessed by the glutathione adducts generated (adduct 2/adducts 1 + 3), in murine lung microsomal incubations was 10:1 and at low concentrations (0.062 mM and below) varied from 13.8:1 to 30:1. In contrast, the ratio of 1R,2S- to 1S,2R-naphthalene oxide produced in murine liver microsomes varied from 1:1 at high substrate concentrations to 5:1 at low substrate concentrations. The ratio of naphthalene oxides was unaffected by the concentration of glutathione in the incubation. In contrast to the preferential formation of 1R,2S-naphthalene oxide observed in mouse lung microsomal preparations, lung microsomes derived from the rat, hamster and monkey yielded 1R,2S- to 1S,2R-epoxide ratios of 0.48, 0.61 and 0.12, respectively, at 0.5 mM naphthalene. Substantial differences in the stereochemistry of naphthalene epoxidation also were noted in incubations of postmitochondrial supernatant from different regions of the nasal mucosa in the mouse, rat and hamster. The olfactory region showed the highest rates of substrate turnover and 1R,2S-naphthalene oxide was the predominant enantiomer formed in preparations from all three species. These studies show a good correlation between the rate and stereochemistry of naphthalene epoxidation with the species, tissue and regional toxicity of naphthalene in the rodent and suggest that primate airways may not be susceptible to naphthalene injury.

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