Detection of phenolic metabolites of styrene in mouse liver and lung microsomal incubations.
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.
Shen
Shuijie
S
Center for Developmental Therapeutics, Seattle Children’s Research Institute, Seattle, Washington 98101, USA.
Zhang
Fan
F
Gao
Lingbo
L
Zeng
Su
S
Zheng
Jiang
J
D000818:Animals; D001711:Biotransformation; D004785:Environmental Pollutants / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D008401:Gas Chromatography-Mass Spectrometry; D006900:Hydroxylation; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D010636:Phenols / Q000032:analysis* / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity; D020058:Styrene / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity
D004785:Environmental Pollutants; D010636:Phenols; D020058:Styrene