Interactions of di- and trihydroxybenzenes with transition metals and their biological consequences

Small dihydroxy- and trihydroxybenzenes are polyphenolic compounds found in plant-based materials and formed by the human gut microbiota from other dietary phenolics. This study aimed to explore how 5 structurally related hydroxybenzenes interact with the biologically relevant metals iron and copper under various (patho)physiological pH conditions, focusing on their chelating and reducing abilities, influence on the metal-driven Fenton reactions, and their role in copper-induced hemolysis. Only compounds with hydroxyl groups in an <i>ortho-</i>position, specifically pyrogallol and 4-methylcatechol, were able to strongly chelate Fe²⁺ at neutral pH and exhibited the largest capacity to reduce Fe³⁺ and Cu²⁺. However, the ability to chelate metals did not translate into inhibition of the Fenton reaction. Only 2,4-dihydroxyacetophenone and resorcinol, compounds with hydroxyl groups in a <i>meta</i>-position that lack chelating capability, were effective in suppressing hydroxyl radical formation triggered by the Fe²⁺-driven Fenton reaction. Interestingly, pyrogallol, despite its strong pro-oxidant properties, was the only compound that protected human erythrocytes from Cu-induced lysis. In conclusion, solely pyrogallol seems to have a protective effect against copper-induced toxicity under biologically relevant conditions.