Stereoselectivity of naphthalene epoxidation by mouse, rat, and hamster pulmonary, hepatic, and renal microsomal enzymes

Alan R Buckpitt, N. Castagnoli, S. D. Nelson, A. D. Jones, L. S. Bahnson

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Abstract

Previous studies have demonstrated the formation of three glutathione conjugates during the hepatic and pulmonary microsomal metabolism of naphthalene in the presence of reduced glutathione and cytosolic enzymes containing the glutathione transferases. These glutathione conjugates now have been identified by negative ion fast atom bombardment mass spectrometry, by proton NMR spectroscopy, and by chemical synthesis from the (1S,2R)- and (1R,2S)-naphthalene 1,2-oxide enantiomers as isomeric hydroxyglutathionyldihydronaphthalene derivatives. All three glutathione adducts yielded prominent mass spectral ions at m/z 450 (M - H)-, 432 (dehydration product), and 306 (glutathionyl moiety) which were consistent with the monoglutathionyl derivatives of hydroxydihydronaphthalene. Signals in the proton NMR spectra at 3.60 and 4.95 ppm (adduct 1) and 3.60 and 4.95 ppm (adduct 2) indicated that these conjugates were diastereomers of 1-hydroxy-2-glutathionyl-1,2-dihydronaphthalene. Corresponding signals for H1 and H2 at 4.22 and 4.45 ppm for adduct 3 showed that this isomer was generated from attack of glutathione at the 1 position of the naphthalene 1,2-oxide. Incubation of synthetic (1S, 2R)-naphthalene 1,2-oxide with glutathione in the presence of glutathione transferases resulted in the formation of adducts 1 and 3 in approximately equal proportions; under identical conditions, glutathione conjugate 2 was formed from (1R, 2S)-naphthalene 1,2-oxide. Incubation of naphthalene, glutathione, and glutathione transferases with pulmonary, hepatic, or renal microsomal preparations from mouse, rat, and hamster resulted in the formation of all three glutathione conjugates. Substantial differences in the rates of formation of the individual conjugates were observed. The (1R,2S)-naphthalene 1,2-oxide isomer was the predominant enantiomer (10:1 ratio) formed by microsomes from mouse lung, which is the major target organ for acute toxicity in this species. In comparison, the relative rates of formation of (1R, 2S)- (adduct 2) to (1S,2R)-naphthalene 1,2-oxide (adducts 1 and 3) in mouse liver and kidney and in rat and hamster tissues were 1:1 or less. These results provide direct evidence for the formation of thio adducts derived from attack of glutathione at the C-1 position of naphthalene 1,2-oxide and suggest that opening of the oxirane ring may proceed with both regio- and enantioselectivity in the glutathione conjugation reaction. In addition, the comparative metabolism studies show that the stereoselectivity of naphthalene epoxidation varies considerably between species and tissues, a factor which may be important in the pathogenesis of acute toxicity caused by naphthalene.

Original languageEnglish (US)
Pages (from-to)491-498
Number of pages8
JournalDrug Metabolism and Disposition
Volume15
Issue number4
StatePublished - 1987

Fingerprint

Stereoselectivity
Epoxidation
Cricetinae
Glutathione
Rats
Kidney
Lung
Liver
Enzymes
Glutathione Transferase
Enantiomers
Metabolism
Isomers
Toxicity
Protons
naphthalene
Ions
Tissue
Fast Atom Bombardment Mass Spectrometry
Derivatives

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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Stereoselectivity of naphthalene epoxidation by mouse, rat, and hamster pulmonary, hepatic, and renal microsomal enzymes. / Buckpitt, Alan R; Castagnoli, N.; Nelson, S. D.; Jones, A. D.; Bahnson, L. S.

In: Drug Metabolism and Disposition, Vol. 15, No. 4, 1987, p. 491-498.

Research output: Contribution to journalArticle

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T1 - Stereoselectivity of naphthalene epoxidation by mouse, rat, and hamster pulmonary, hepatic, and renal microsomal enzymes

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AU - Jones, A. D.

AU - Bahnson, L. S.

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N2 - Previous studies have demonstrated the formation of three glutathione conjugates during the hepatic and pulmonary microsomal metabolism of naphthalene in the presence of reduced glutathione and cytosolic enzymes containing the glutathione transferases. These glutathione conjugates now have been identified by negative ion fast atom bombardment mass spectrometry, by proton NMR spectroscopy, and by chemical synthesis from the (1S,2R)- and (1R,2S)-naphthalene 1,2-oxide enantiomers as isomeric hydroxyglutathionyldihydronaphthalene derivatives. All three glutathione adducts yielded prominent mass spectral ions at m/z 450 (M - H)-, 432 (dehydration product), and 306 (glutathionyl moiety) which were consistent with the monoglutathionyl derivatives of hydroxydihydronaphthalene. Signals in the proton NMR spectra at 3.60 and 4.95 ppm (adduct 1) and 3.60 and 4.95 ppm (adduct 2) indicated that these conjugates were diastereomers of 1-hydroxy-2-glutathionyl-1,2-dihydronaphthalene. Corresponding signals for H1 and H2 at 4.22 and 4.45 ppm for adduct 3 showed that this isomer was generated from attack of glutathione at the 1 position of the naphthalene 1,2-oxide. Incubation of synthetic (1S, 2R)-naphthalene 1,2-oxide with glutathione in the presence of glutathione transferases resulted in the formation of adducts 1 and 3 in approximately equal proportions; under identical conditions, glutathione conjugate 2 was formed from (1R, 2S)-naphthalene 1,2-oxide. Incubation of naphthalene, glutathione, and glutathione transferases with pulmonary, hepatic, or renal microsomal preparations from mouse, rat, and hamster resulted in the formation of all three glutathione conjugates. Substantial differences in the rates of formation of the individual conjugates were observed. The (1R,2S)-naphthalene 1,2-oxide isomer was the predominant enantiomer (10:1 ratio) formed by microsomes from mouse lung, which is the major target organ for acute toxicity in this species. In comparison, the relative rates of formation of (1R, 2S)- (adduct 2) to (1S,2R)-naphthalene 1,2-oxide (adducts 1 and 3) in mouse liver and kidney and in rat and hamster tissues were 1:1 or less. These results provide direct evidence for the formation of thio adducts derived from attack of glutathione at the C-1 position of naphthalene 1,2-oxide and suggest that opening of the oxirane ring may proceed with both regio- and enantioselectivity in the glutathione conjugation reaction. In addition, the comparative metabolism studies show that the stereoselectivity of naphthalene epoxidation varies considerably between species and tissues, a factor which may be important in the pathogenesis of acute toxicity caused by naphthalene.

AB - Previous studies have demonstrated the formation of three glutathione conjugates during the hepatic and pulmonary microsomal metabolism of naphthalene in the presence of reduced glutathione and cytosolic enzymes containing the glutathione transferases. These glutathione conjugates now have been identified by negative ion fast atom bombardment mass spectrometry, by proton NMR spectroscopy, and by chemical synthesis from the (1S,2R)- and (1R,2S)-naphthalene 1,2-oxide enantiomers as isomeric hydroxyglutathionyldihydronaphthalene derivatives. All three glutathione adducts yielded prominent mass spectral ions at m/z 450 (M - H)-, 432 (dehydration product), and 306 (glutathionyl moiety) which were consistent with the monoglutathionyl derivatives of hydroxydihydronaphthalene. Signals in the proton NMR spectra at 3.60 and 4.95 ppm (adduct 1) and 3.60 and 4.95 ppm (adduct 2) indicated that these conjugates were diastereomers of 1-hydroxy-2-glutathionyl-1,2-dihydronaphthalene. Corresponding signals for H1 and H2 at 4.22 and 4.45 ppm for adduct 3 showed that this isomer was generated from attack of glutathione at the 1 position of the naphthalene 1,2-oxide. Incubation of synthetic (1S, 2R)-naphthalene 1,2-oxide with glutathione in the presence of glutathione transferases resulted in the formation of adducts 1 and 3 in approximately equal proportions; under identical conditions, glutathione conjugate 2 was formed from (1R, 2S)-naphthalene 1,2-oxide. Incubation of naphthalene, glutathione, and glutathione transferases with pulmonary, hepatic, or renal microsomal preparations from mouse, rat, and hamster resulted in the formation of all three glutathione conjugates. Substantial differences in the rates of formation of the individual conjugates were observed. The (1R,2S)-naphthalene 1,2-oxide isomer was the predominant enantiomer (10:1 ratio) formed by microsomes from mouse lung, which is the major target organ for acute toxicity in this species. In comparison, the relative rates of formation of (1R, 2S)- (adduct 2) to (1S,2R)-naphthalene 1,2-oxide (adducts 1 and 3) in mouse liver and kidney and in rat and hamster tissues were 1:1 or less. These results provide direct evidence for the formation of thio adducts derived from attack of glutathione at the C-1 position of naphthalene 1,2-oxide and suggest that opening of the oxirane ring may proceed with both regio- and enantioselectivity in the glutathione conjugation reaction. In addition, the comparative metabolism studies show that the stereoselectivity of naphthalene epoxidation varies considerably between species and tissues, a factor which may be important in the pathogenesis of acute toxicity caused by naphthalene.

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