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Basic toxicokinetics

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basic toxicokinetics in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study with well described method.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
no guideline available
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:

Results and discussion

Applicant's summary and conclusion

Executive summary:

The purpose of this study was to investigate selected aspects of the metabolism of 4-vinylphenol, a hepatotoxic and pneumotoxic metabolite of styrene. In a previous study, two oxidative metabolites of 4VP were identified during incubations of styrene with mouse lung microsomes (Metabolites B and E). The first objective of the current study was to verify the structure of metabolite B, the 3,4-catechol of styrene. The structure was verified. The second objective was to directly characterize the CYPs responsible for epoxidation of 4-VP to form Metabolite E, the 4 VP-epoxide (4-VPO). Experiments with 5-phenyl-1-pentyne (5P1P), an inhibitor of CYP 2F2, and diethyldithiocarbamate (DDTC), an inhibitor of CYP 2E1, were conducted and 4-VPO formation was evaluated in mouse, rat, and human donor lung microsomes. Both inhibitors decreased the yield of the 4-VPO trapped GSH conjugates across species and tissues tested. The inhibitor 5P1P had a greater inhibitory effect in the mouse lung than DDTC (85% vs. 57%), suggesting that 2F2 was primarily responsible for 4-VPO formation in the mouse lung. Not all of the apparent DDTC inhibitory effects seen in this study are due to direct inhibition of CYP 2E1, since DDTC was found to directly react with 4-VPO. Thus, further evidence was developed showing CYP 2F2 was responsible for the formation of 4-VPO in mouse lung. The third objective of this study was to evaluate the regioselectivity of glutathione (GSH) addition to 4-VPO. Using a synthetic standard of 4-VPO, two regio-isomers of 4-VPO-GSH conjugates were isolated and identified as R and S enantiomers of the C1-regioisomer of 4-VPO-GSH. The two enantiomers of the C2-4-VPO-GSH metabolites were isolated, but not fully characterized. There was no species or tissue difference in the regio- or stereoselectivity of 4VPO-GSH formation. This study provides better insight on the chemicals responsible for the lung toxicity seen with 4-VP and possibly styrene.