Oxidative Metabolism of BDE-99 by Human Liver Microsomes: Predominant Role of CYP2B6
| العنوان: | Oxidative Metabolism of BDE-99 by Human Liver Microsomes: Predominant Role of CYP2B6 |
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| المؤلفون: | Claudio Erratico, Stelvio M. Bandiera, András Szeitz |
| المصدر: | Toxicological Sciences. 129:280-292 |
| بيانات النشر: | Oxford University Press (OUP), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | CYP2B6, Metabolite, Biology, Hydroxylation, Toxicology, chemistry.chemical_compound, Polybrominated diphenyl ethers, Biotransformation, Tandem Mass Spectrometry, Halogenated Diphenyl Ethers, Humans, Primary metabolite, Cytochrome P450, Oxidoreductases, N-Demethylating, Recombinant Proteins, Cytochrome P-450 CYP2B6, Kinetics, chemistry, Biochemistry, Biocatalysis, Microsomes, Liver, biology.protein, Microsome, Aryl Hydrocarbon Hydroxylases, Oxidation-Reduction, Chromatography, Liquid |
| الوصف: | Hydroxylated polybrominated diphenyl ethers (PBDEs) have been found in human serum, suggesting that they are formed by in vivo oxidative metabolism of PBDEs. However, the biotransformation of 2,2',4,4',5-pentabromodiphenyl ether (BDE-99), a major PBDE detected in human tissue and environmental samples, is poorly understood. In the present study, the oxidative metabolism of BDE-99 was assessed using pooled and single-donor human liver microsomes, a panel of human recombinant cytochrome P450 (CYP) enzymes, and CYP-specific antibodies. Hydroxylated metabolites were quantified using a liquid chromatography/tandem mass spectrometry-based method. In total, 10 hydroxylated metabolites of BDE-99 were produced by human liver microsomes. Six metabolites were identified as 2,4,5-tribromophenol (2,4,5-TBP), 4-OH-BDE-90, 5'-OH-BDE-99, 6'-OH-BDE-99, 4'-OH-BDE-101, and 2-OH-BDE-123 using authentic standards. Three monohydroxy- and one dihydroxy-pentabrominated metabolites were unidentified. Rates of formation of the three major metabolites (2,4,5-TBP, 5'-OH-BDE-99, and 4'-OH-BDE-101) by human liver microsomes ranged from 24.4 to 44.8 pmol/min/mg protein. Additional experiments demonstrated that the dihydroxylated metabolite was a primary metabolite of BDE-99 and was not produced by hydroxylation of a monohydroxy metabolite. Among the panel of recombinant CYP enzymes tested, formation of all 10 hydroxylated metabolites was catalyzed solely by CYP2B6. A combined approach using antibodies to CYP2B6 and single-donor liver microsomes expressing a wide range of CYP2B6 levels confirmed that CYP2B6 was responsible for the biotransformation of BDE-99. Collectively, the results show that the oxidative metabolism of BDE-99 by human liver microsomes is catalyzed solely by CYP2B6 and is an important determinant of the toxicity and bioaccumulation of BDE-99 in humans. |
| تدمد: | 1096-0929 1096-6080 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::10c96e49362436b1a221b89ba9822130 https://doi.org/10.1093/toxsci/kfs215 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....10c96e49362436b1a221b89ba9822130 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10960929 10966080 |
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