Abstract
Metabolic activation is considered to be a critical step for styrene-induced pulmonary toxicity. Styrene-7,8-oxide is a primary oxidative metabolite generated by vinyl epoxidation of styrene. In addition, urinary 4-vinylphenol (4-VP), a phenolic metabolite formed by aromatic hydroxylation, has been detected in workers and experimental animals after exposure to styrene. In the present study, new oxidative metabolites of styrene, including 2-vinylphenol (2-VP), 3-vinylphenol (3-VP), vinyl-1,4-hydroquinone, and 2-hydroxystyrene glycol were detected in mouse liver microsomal incubations. The production rates of 2-VP, 3-VP, 4-VP, and styrene glycol were 0.0527 ± 0.0045, 0.0019 ± 0.0006, 0.0053 ± 0.0002, and 4.42 ± 0.33 nmol/(min · mg protein) in mouse liver microsomes, respectively. Both disulfiram (100 μM) and 5-phenyl-1-pentyne (5 μM) significantly inhibited the formation of the VPs and styrene glycol. 2-VP, 3-VP, and 4-VP were metabolized in mouse liver microsomes at rates of 2.50 ± 0.30, 2.63 ± 0.13, and 3.45 ± 0.11 nmol/(min · mg protein), respectively. The three VPs were further metabolized to vinylcatechols and/or vinyl-1,4-hydroquinone and the corresponding glycols. Pulmonary toxicity of 2-VP, 3-VP, and 4-VP was evaluated in CD-1 mice, and 4-VP was found to be more toxic than 2-VP and 3-VP.
Footnotes
This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL080226].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.033522.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
-
ABBREVIATIONS:
- SO
- styrene-7,8-oxide
- VP
- vinylphenol
- 4-VP
- 4-vinylphenol
- 3-VP
- 3-vinylphenol
- 2-VP
- 2-vinylphenol
- P450
- cytochrome P450
- 5P1P
- 5-phenyl-1-pentyne
- BSTFA
- N,O-bis(trimethylsilyl)trifluoroacetamide
- GC/MS
- gas chromatography/mass spectrometry
- TLC
- thin-layer chromatography
- TMS
- trimethylsilane
- THF
- tetrahydrofuran
- SG
- styrene glycol
- SIM
- selected ion monitoring
- BALF
- bronchoalveolar lavage fluid
- LDH
- lactate dehydrogenase.
- Received March 23, 2010.
- Accepted August 19, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|