Detection of Phenolic Metabolites of Styrene in Mouse Liver and Lung Microsomal Incubations

Shen, Shuijie; Zhang, Fan; Gao, Lingbo; Zeng, Su; Zheng, Jiang

doi:10.1124/dmd.110.033522

Cited by 5 publications

(13 citation statements)

References 27 publications

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“…Although M3 was a minor metabolite (<0.5%) in human liver microsomes, it was the main metabolite in human recombinant CYP3A4, due to the over‐expression of CYP3A4 activity and an absence of competing enzymes and reactions in the cDNA‐expressed enzyme. The mechanism of the major metabolite M1 (dihydroxylation) in liver microsomes is proposed as the alkene of the acryloyl group was preferentially metabolized to the epoxide by CYP3A4 and hydrolyzed by epoxide hydrolase …”

Section: Resultsmentioning

confidence: 99%

Metabolite identification of a new tyrosine kinase inhibitor, HM781‐36B, and a pharmacokinetic study by liquid chromatography/tandem mass spectrometry

Kim

Suh

et al. 2013

Rapid Comm Mass Spectrometry

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Section: Resultsmentioning

confidence: 99%

Metabolite identification of a new tyrosine kinase inhibitor, HM781‐36B, and a pharmacokinetic study by liquid chromatography/tandem mass spectrometry

Kim

Suh

et al. 2013

Rapid Comm Mass Spectrometry

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“…Styrene glycol- d 8 (SG- d 8 ), 2-VP, and 3-VP were synthesized in our lab. 19 An HP 5890 Series II gas chromatograph with a capillary GC column (J&W Scientific BD-5MS, 20 m × 0.18 mm id, film thickness 0.18 µm), an HP 5971A mass-selective detector (MSD), and an HP 7673 autosampler was used to analyze metabolite samples. HP Chemstation B.02.05 software was used for GC/MS control and data collection.…”

Section: Methodsmentioning

confidence: 99%

“…4-VP has been reported more toxic than SO, 21,22 and our earlier study also showed that 4-VP was more toxic than 2-VP and 3-VP in mice. 19 The VPs were further metabolized to the corresponding hydroxystyrene oxides, vinylcatechols, and/or vinylhydroquinone in mouse microsomes, 19 but whether these metabolites cause cytotoxicity remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of Styrene to Styrene Oxide and Vinylphenols in Cytochrome P450 2F2- and P450 2E1-Knockout Mouse Liver and Lung Microsomes

Shen

Ding

et al. 2013

Chem. Res. Toxicol.

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Pulmonary toxicity of styrene is initiated by cytochromes P450-dependent metabolic activation. P450 2E1 and P450 2F2 are considered to be two main cytochrome P450 (CYP) enzymes responsible for styrene metabolism in mice. The objective of the current study was to determine the correlation between the formation of styrene metabolites (i.e. styrene oxide and 4-vinylphenol) and pulmonary toxicity of styrene, using Cyp2e1- and Cyp2f2-null mouse models. Dramatic decrease in the formation of styrene glycol and 4-vinylphenol was found in Cyp2f2-null mouse lung microsomes, relative to that in the wild-type mouse lung microsomes. However, no significant difference in the production of the styrene metabolites was observed between lung microsomes obtained from Cyp2e1-null and the wild-type mice. The knock–out and wild-type mice were treated with styrene (6.0 mmol/kg, ip), and cell counts and LDH activity in bronchoalveolar lavage fluids were monitored to evaluate the pulmonary toxicity induced by styrene. Cyp2e1-null mice displayed similar susceptibility to lung toxicity of styrene as the wild-type animals. However, Cyp2f2-null mice were resistant to styrene-induced pulmonary toxicity. In conclusion, both P450 2E1 and P450 2F2 are responsible for the metabolic activation of styrene. The latter enzyme plays an important role in styrene-induced pulmonary toxicity. Both styrene oxide and 4-vinylphenol are suggested to participate in the development of lung injury induced by styrene.

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“…Enzyme kinetic studies were performed following the protocol established in our lab (Shen et al ., 2010). Briefly, a 0.5 mL solution containing recombinant human CYP2E1 (50 pmol), 5 mM MgCl 2 , and 2 mM NADPH in 50 mM phosphate buffer (pH 7.4) was preincubated in a 37 °C water bath shaker for 3 min.…”

Section: Methodsmentioning

confidence: 99%

“…The reaction was initiated by addition of 5.0 μL of various concentrations of styrene, 4-fluorostyrene, 4-chlorostyrene or 4-bromostyrene (final concentration: 0.1–100 μM). The incubation continued for 20 min and was quenched by addition of the same volume of ethyl acetate, followed by spiking with deuterated styrene glycol (styrene glycol- d 8 , prepared in our lab) as internal standard (Shen et al ., 2010). The resulting mixture was vortexed and the organic phase was collected.…”

Section: Methodsmentioning

confidence: 99%

Structure-toxicity relationship study of para-halogenated styrene analogues in CYP2E1 transgenic cells

Chung¹,

Shen²,

Jiang³

et al. 2012

Toxicology Letters

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Styrene is one of the most important industrial intermediates consumed in the world and is mainly used as a monomer for reinforced plastics and rubber. Styrene has been found to be hepatotoxic and pneumotoxic in humans and experimental animals. The toxicity of styrene is suggested to be metabolism-dependent. Styrene-7,8-oxide has been considered as the major metabolite responsible for styrene-induced cytotoxicity. The objective of the study was to investigate the correlation between cytotoxicity of styrene and chemical and biochemical properties of the vinyl group of styrene by development of structure activity relationships (SAR). 4-Fluorostyrene, 4-chlorostyrene and 4-bromostyrene were selected for the SAR study. Cytotoxicity of styrene and the halogenated styrene derivatives with an order of 4-bromostyrene > 4-chlorostyrene > 4-fluorostyrene ≈ styrene was observed in CYP2E1 transgenic cells. Similar orders in the efficiency of the metabolism of styrene and the halogenated styrene analogues to their oxides and in the electrophilicity of the corresponding oxides were observed. Additionally, the order of the potency of cellular glutathione depletion and the degree of protein adduction induced by styrene and the halogenated styrenes were consistent with that of their cytotoxicities. The wild-type cells were less susceptible to the toxicity of the corresponding model compounds than CYP2E1 cells. The present study provided insight into the roles of the biochemical and chemical properties of styrene in its cytotoxicity.

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Detection of Phenolic Metabolites of Styrene in Mouse Liver and Lung Microsomal Incubations

Cited by 5 publications

References 27 publications

Metabolite identification of a new tyrosine kinase inhibitor, HM781‐36B, and a pharmacokinetic study by liquid chromatography/tandem mass spectrometry

Metabolite identification of a new tyrosine kinase inhibitor, HM781‐36B, and a pharmacokinetic study by liquid chromatography/tandem mass spectrometry

Metabolism of Styrene to Styrene Oxide and Vinylphenols in Cytochrome P450 2F2- and P450 2E1-Knockout Mouse Liver and Lung Microsomes

Structure-toxicity relationship study of para-halogenated styrene analogues in CYP2E1 transgenic cells

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