Background: Metabolic transformations of phenolic compounds in in vitro models may alter the structure of molecules present in the cell media, entailing the existence of a dynamic scenario and conditioning the bioactivity of the tested compounds. Nevertheless, most of the bioactivity studies carried out with cells do not evaluate these potentially confounding reactions. Scope and Approach: The metabolic fate of phenolic compounds in contact with different cell lines has been reviewed to highlight the importance of cell metabolism when testing the biological properties of phenolic metabolites. The review is divided in two main blocks. The first one summarizes the transformation of the main groups of phenolic compounds by intestinal and hepatic cells. The second one is devoted to the transformation of some phenolic metabolites in cell models corresponding to peripheral tissues. Some practical recommendations are also provided to assist future researchers in the field. Key Findings and Conclusions: The occurrence of newly-formed metabolites in cell experiments seems to be cell type- and compound-specific. Metabolic reactions occurring in cell experimental models may represent a limiting or promoting step to elicit bioactivity. They may be relevant for understanding the molecules and mechanisms responsible for the biological effects of phenolic metabolites. Therefore, the analysis of the cell media/lysates used in bioactivity experiments is a paramount step to fully clarify the real metabolites behind the observed bioactivity. Future in vitro research should take into account the assessment of cellular metabolism of phenolic bioactives.
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