In vitro metabolism, glutathione conjugation, and CYP isoform specificity of epoxidation of 4-vinylphenol

Abstract

1. 4-Vinylphenol (4VP) has been identified as a minor urinary metabolite of styrene in rat and human volunteers. This compound has been shown to be more hepatotoxic and pneumotoxic than both styrene and styrene oxide at lower doses in rats and mice. To explore the possible toxicity mechanism of 4VP, the current study was conducted to investigate the metabolism of 4VP, the glutathione (GSH) conjugation of the metabolites of 4VP and its cytochrome P₄₅₀ (CYP) specificity in epoxidation in different microsomes in vitro.

2. Incubations of 4VP with mouse lung microsomes afforded two major metabolites which were identified as 4-(2-oxiranyl)-phenol of 4VP (4VPO) and 4VP catechol. 4VPO was found to react with GSH to form GSH conjugate and 4VP catechol was found to further be metabolized to electrophilic species which react with GSH to form the corresponding 4VP catechol GSH conjugates. Relative formation rates for those GSH conjugates and the regioisomer formation of 4VPO-GSH conjugates with both inhibitors of CYP 2F2 and CYP 2E1 in microsomal incubation condition were also investigated.

3. This present study provides better insight on the lung toxicity seen with 4VP, the toxic metabolite of commercial styrene.

Keywords::

• 4-vinylphenol
• glutathione conjugation
• CYP inhibition
• microsomal incubation

Acknowledgements

The author wish to thank Lynn Kan for microsomal preparations and Rebecca Drury for document preparations. Funding for this study was provided by Cefic SSC and the Styrene Information and Research Center (SIRC). The authors wish to thank Kimberley Anklam for her technical assistance during this study.

Declaration of interest

Fagen Zhang, Ezra R. Lowe, David L. Rick, Xiaohua, Qiu, and Michael J. Bartels work for the company that makes the precursor (styrene) of 4-vinylphenol.