Abstract
We previously demonstrated that estrogenic activity of bisphenol A (BPA) in the yeast estrogen screening assay was increased severalfold after incubation with rat liver S9 fraction in the presence of a NADPH-generating system. In this study, we investigated whether eight BPA-related compounds are similarly activated metabolically by rat liver S9 fraction. Three of the analogs exhibited an increase of estrogenic activity after incubation with rat liver S9 fraction but not with microsomal or cytosolic fraction alone. The structures of the metabolites formed were examined by liquid chromatography/mass spectrometry. In addition to oxidized metabolites such as catechols, we found novel dimer-type metabolites. Some of the putative metabolites were chemically synthesized to confirm their structures. The structural requirements for formation of the metabolites, some of which showed more potent estrogenic activity than the parent substrates, were examined. We have uncovered a new pathway of metabolic activation of certain phenolic compounds, such as BPA analogs, to estrogenic dimer-type compounds.
Footnotes
This study was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan [Grant-in-Aid for Young Scientists (B) 18710057].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040121.
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ABBREVIATIONS:
- BPA
- bisphenol A
- MBP
- 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene
- EDC
- endocrine-disrupting chemical
- BPB
- bisphenol B, 2,2-bis(4-hydroxyphenyl)butane)
- DMBPA
- 3,3′-dimethylbisphenol A, 2,2-bis(3-methyl-4-hydroxyphenyl)propane)
- TMBPA
- 3,3′,5,5′-tetramethylbisphenol A, 2,2-bis(3,5-dimethyl-4-hydroxyphenyl)propane)
- BPF
- bisphenol F, 4,4′-dihydroxydiphenylmethane
- BPAD
- bisphenol AD, ethylidenebisphenol
- LC
- liquid chromatography
- MS
- mass spectrometry
- BPCH
- 1,1-bis(4-hydroxyphenyl)cyclohexane
- CP
- 4-α-cumylphenol
- DP
- 2,2-diphenylpropane
- CPRG
- chlorophenol red-β-galactopyranoside
- YES
- yeast estrogen screening
- P450
- cytochrome P450
- HPLC
- high-performance liquid chromatography
- OD
- optical density
- ESI
- electrospray ionization.
- Received April 19, 2011.
- Accepted June 2, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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