Inhibition of Human Liver Carboxylesterase (hCE1) by Organophosphate Ester Flame Retardants and Plasticizers: Implications for Pharmacotherapy
| Autor: | Heather M. Stapleton, Allison L. Phillips |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Chromatography Organophosphate Plasticizer 010501 environmental sciences Prodrug Toxicology 01 natural sciences 03 medical and health sciences Carboxylesterase chemistry.chemical_compound 030104 developmental biology Enzyme chemistry Imidapril medicine Exposure Sciences 0105 earth and related environmental sciences medicine.drug Triphenyl phosphate Fire retardant |
| Zdroj: | Toxicol Sci |
| ISSN: | 1096-0929 1096-6080 |
| Popis: | Organophosphate ester (OPE) flame retardants and plasticizers, consumer product additives with widespread human exposure, were evaluated for their effect on the activity of purified human liver carboxylesterase (hCE1). Four of the 15 OPEs tested had IC50 values lower than 100 nM, including triphenyl phosphate (TPHP), 2-ethylhexyl diphenyl phosphate (EHDPHP), 4-isopropylphenyl diphenyl phosphate (4IPPDPP), and 4-tert-butylphenyl diphenyl phosphate (4tBPDPP), as did 4 of the commercial flame retardant mixtures tested. Because hCE1 is critical for the activation of imidapril, an angiotensin-converting enzyme-inhibitor prodrug prescribed to treat hypertension, the most potent inhibitors, TPHP and 4tBPDPP, and an environmentally relevant mixture (house dust) were further evaluated for their effect on imidapril bioactivation in vitro. TPHP and 4tBPDPP were potent inhibitors of hCE1-mediated imidapril activation (Ki = 49.0 and 17.9 nM, respectively). House dust extracts (100 µg/ml) also caused significant reductions (up to 33%) in imidapril activation. Combined, these data suggest that exposure to OPEs may affect pharmacotherapy. |
| Databáze: | OpenAIRE |
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