New insight into molecular mechanism of P450-Catalyzed metabolism of emerging contaminants and its consequence for human health: A case study of preservative methylparaben

Abstract

Hydroxylated metabolites in the living body are considered as a potential biomarker of exposure to emerging contaminations (ECs) and breast cancer, but their formation mechanism has not received enough attention. Besides, the adverse impacts of metabolites during the metabolic transformation of ECs largely remain unknown. In this study, we employed a density functional calculation combing with in-vitro incubation of human liver microsomes to explore the bio-transformation of preservative methylparaben (MPB) in human bodies. Our results showed that hydroxylated metabolites of MPB (OH-MPB) were observed experimentally, while a formation mechanism was revealed at the molecular level. That is, hydroxylated metabolite was exclusively formed via the hydrogen abstraction from the phenolic hydroxyl group of MPB followed by the OH-rebound pathway, rather than the direct hydroxylation on the benzene ring. The increasing of hydroxyl groups on ECs could improve the metabolisms. This was confirmed in the metabolism of ECs without hydroxyl group and with multiple-hydroxyl groups, respectively. Furthermore, toxicity assessments show that compared to parent MPB, the hydroxylated metabolites have increased negative impacts on the gastrointestinal system and liver. A semiquinone product exhibits potential damage in the cardiovascular system and epoxides are toxic to the blood and gastrointestinal system. The findings deepen our insight into the biotransformation of parabens in human health, especially by providing health warnings about the potential impacts caused by semiquinone and epoxides.

Keywords

• Parabens
• P450 enzymes
• Metabolic mechanism
• Hydroxylation products
• Health risk