Characterisation of the toxic metabolite(s) of naphthalene

Andrew S. Wilson, Carl D. Davis, Dominic P. Williams, Alan R Buckpitt, Munir Pirmohamed, B. Kevin Park

Research output: Contribution to journalArticle

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Abstract

The toxicity of naphthalene and its metabolites has been investigated in vitro. Both naphthalene and its metabolite 1-naphthol were bioactivated by human hepatic microsomes to metabolite(s) which were toxic to mononuclear leucocytes (MNL). However, 1-naphthol was more cytotoxic than naphthalene (49.8 ± 13.9% vs. 19.0 ± 10.0% cell death; P < 0.01), indicating that the toxicity of naphthalene is dependent on the bioactivation of 1-naphthol. CYP2E1-induced rat liver microsomes increased metabolism of naphthalene by 13% compared to control microsomes with a concomitant increase in both 1-naphthol and dihydrodiol formation. The cytotoxicity of naphthalene but not of 1-naphthol was increased by CYP2E1 induction, indicating that separate enzymes are involved in the bioactivation of 1-naphthol. The metabolites of 1-naphthol, 1,2-naphthoquinone (51.4 ± 6.6% cell death) and 1,4-naphthoquinone (49.1 ± 3.4% cell death) were directly toxic to MNL and depleted glutathione to 1.0% of the control levels. Both quinones were also and enotoxic to human lymphocytes. In contrast, the primary metabolite of naphthalene, the 1,2-epoxide (0-100 μM) was neither cytotoxic nor genotoxic, and did not deplete glutathione. In conclusion, our data suggests that the cytotoxicity and genotoxicity of naphthalene is associated with the formation of quinones from 1-naphthol rather than naphthalene-1,2-epoxide.

Original languageEnglish (US)
Pages (from-to)233-242
Number of pages10
JournalToxicology
Volume114
Issue number3
DOIs
StatePublished - Dec 18 1996

Fingerprint

Poisons
Metabolites
Cell death
Mononuclear Leukocytes
Cytochrome P-450 CYP2E1
Quinones
Cell Death
Epoxy Compounds
Cytotoxicity
Microsomes
Glutathione
Toxicity
naphthalene
Lymphocytes
1-naphthol
Level control
Liver Microsomes
Metabolism
Liver
Rats

Keywords

  • 1-Naphthol
  • CYP2E1
  • Naphthalene
  • Naphthalene 1,2-epoxide
  • Naphthoquinones
  • Toxicity

ASJC Scopus subject areas

  • Toxicology

Cite this

Wilson, A. S., Davis, C. D., Williams, D. P., Buckpitt, A. R., Pirmohamed, M., & Park, B. K. (1996). Characterisation of the toxic metabolite(s) of naphthalene. Toxicology, 114(3), 233-242. https://doi.org/10.1016/S0300-483X(96)03515-9

Characterisation of the toxic metabolite(s) of naphthalene. / Wilson, Andrew S.; Davis, Carl D.; Williams, Dominic P.; Buckpitt, Alan R; Pirmohamed, Munir; Park, B. Kevin.

In: Toxicology, Vol. 114, No. 3, 18.12.1996, p. 233-242.

Research output: Contribution to journalArticle

Wilson, AS, Davis, CD, Williams, DP, Buckpitt, AR, Pirmohamed, M & Park, BK 1996, 'Characterisation of the toxic metabolite(s) of naphthalene', Toxicology, vol. 114, no. 3, pp. 233-242. https://doi.org/10.1016/S0300-483X(96)03515-9
Wilson AS, Davis CD, Williams DP, Buckpitt AR, Pirmohamed M, Park BK. Characterisation of the toxic metabolite(s) of naphthalene. Toxicology. 1996 Dec 18;114(3):233-242. https://doi.org/10.1016/S0300-483X(96)03515-9
Wilson, Andrew S. ; Davis, Carl D. ; Williams, Dominic P. ; Buckpitt, Alan R ; Pirmohamed, Munir ; Park, B. Kevin. / Characterisation of the toxic metabolite(s) of naphthalene. In: Toxicology. 1996 ; Vol. 114, No. 3. pp. 233-242.
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abstract = "The toxicity of naphthalene and its metabolites has been investigated in vitro. Both naphthalene and its metabolite 1-naphthol were bioactivated by human hepatic microsomes to metabolite(s) which were toxic to mononuclear leucocytes (MNL). However, 1-naphthol was more cytotoxic than naphthalene (49.8 ± 13.9{\%} vs. 19.0 ± 10.0{\%} cell death; P < 0.01), indicating that the toxicity of naphthalene is dependent on the bioactivation of 1-naphthol. CYP2E1-induced rat liver microsomes increased metabolism of naphthalene by 13{\%} compared to control microsomes with a concomitant increase in both 1-naphthol and dihydrodiol formation. The cytotoxicity of naphthalene but not of 1-naphthol was increased by CYP2E1 induction, indicating that separate enzymes are involved in the bioactivation of 1-naphthol. The metabolites of 1-naphthol, 1,2-naphthoquinone (51.4 ± 6.6{\%} cell death) and 1,4-naphthoquinone (49.1 ± 3.4{\%} cell death) were directly toxic to MNL and depleted glutathione to 1.0{\%} of the control levels. Both quinones were also and enotoxic to human lymphocytes. In contrast, the primary metabolite of naphthalene, the 1,2-epoxide (0-100 μM) was neither cytotoxic nor genotoxic, and did not deplete glutathione. In conclusion, our data suggests that the cytotoxicity and genotoxicity of naphthalene is associated with the formation of quinones from 1-naphthol rather than naphthalene-1,2-epoxide.",
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