RESUMEN
Butylated hydroxytoluene (BHT) and its analogs, butylated hydroxyanisole (BHA) and tert-butyl-hydroquinone (TBHQ), are widely used synthetic preservatives to inhibit lipid oxidation in the food, cosmetic and pharmaceutical industries. Despite their widespread use, little is known about their human exposure and related biotransformation products. The metabolism of these compounds was investigated using in vitro incubations with human and rat liver fractions. Liquid chromatography coupled to high-resolution tandem mass spectrometry was employed to detect and characterize stable and reactive species formed via oxidative metabolism, as well as phase II conjugates. Several oxidative metabolites have been detected, as well as glutathione, glucuronide, and sulfate conjugates, many of which were not previously reported. A combination of accurate mass measurements, MS/MS fragmentation behavior, and isotope-labeling studies were used to elucidate metabolite structures.
Asunto(s)
Antioxidantes/análisis , Hidroxianisol Butilado/metabolismo , Hidroxitolueno Butilado/metabolismo , Animales , Antioxidantes/química , Hidroxianisol Butilado/análogos & derivados , Hidroxianisol Butilado/química , Hidroxitolueno Butilado/análogos & derivados , Hidroxitolueno Butilado/química , Cromatografía Liquida , Glucurónidos/análisis , Glutatión/análisis , Humanos , Técnicas In Vitro , Microsomas/metabolismo , Fenoles/análisis , Fenoles/metabolismo , Ratas , Sulfatos/análisis , Espectrometría de Masas en TándemRESUMEN
Bisphenol A (BPA) metabolism has been investigated using several in vitro models, including human and rat liver microsomes and subcellular (S9) fractions, as well as human-recombinant cytochrome P450 3A4 (CYP3A4) expressed in Supersomes, for a comprehensive look at all possible metabolic pathways. By an untargeted approach using liquid chromatography coupled to a high-resolution quadrupole-time-of-flight mass spectrometer, we were able to detect a large number of known Phase I and Phase II metabolites of BPA, as well as several previously uncharacterized ones. A detailed fragmentation study of BPA and its detected metabolites was crucial to confirm structures. Isotope-labeled BPA analogs were highly useful for the structural elucidation of many metabolites. These results contribute to a better understanding of BPA metabolism, including pathways that may introduce additional toxicity, as well as help with the assessment of BPA exposure in different biological matrices.