Urolithin D: A promising metabolite of ellagitannin in combatting oxidative stress

Abstract

The objective of this research is to examine the function of urolithin D (UroD, 3,4,8,9-tetrahydroxy-6H-benzo[c]chromen-6-one), a metabolite obtained from ellagitannins, in the mitigation of oxidative stress. The research is based on estimating the mechanisms through which UroD acts as an antioxidant under physiological conditions, emphasizing standard antioxidant mechanisms such as formal Hydrogen Aatom Transfer (f-HAT), Radical Adduct Formation (RAF)/Radical Coupling Formation (RCF), and Single Electron Transfer followed by Proton Transfer (SET-PT). This study utilised advanced quantum mechanical techniques, specifically density functional theory (DFT) and the Quantum Mechanics-based test for Overall free Radical Scavenging activity (QM-ORSA) methodology, to assess the thermodynamic and kinetic parameters of UroD in the presence of reactive radical species HOO^•, CH₃OO^• and CCl₃OO^•. The estimated overall rate constants (k_overall) indicate a reactivity order of CCl₃OO^• (k_overall = 2.06 × 10¹⁰ M⁻¹s⁻¹) > HOO^• (k_overall = 2.59 × 10⁹ M⁻¹s⁻¹) > CH₃OO^• (k_overall = 1.89 × 10⁹ M⁻¹s⁻¹). The examination of the relative proportions of products (%) indicates that UroD exhibits antiradical action primarily through all examined mechanisms, with the predominant involvement of mononion and dianion acid-base species. In addition to its capacity to directly counteract ROS, UroD can restore oxidative DNA damage, specifically targeting oxidative byproducts commonly associated with 2-deoxyguanosine (2 dG), which are susceptible to oxidative stress. The UroD regenerates G-centered radical cations (2 dG^•+) through the SET mechanism, C-centered radicals (2 dG^•) in the sugar moiety through f-HAT, and repairs i-OH-2dG lesions through sequential hydrogen atom transfer dehydration (SHATD). Additionally, the radical products formed during antioxidant action can be regenerated in the presence of O₂^•− into anionic species, which are subsequently protonated into neutral species that can re-engage in antioxidant activity. These findings underscore the efficiency of UroD in scavenging free radicals and suggest its potential role in preserving cellular integrity and protecting against oxidative stress-related diseases.