Integrating Diphenyl Diselenide and Its MeHg⁺ Detoxificant Mechanism on a Conceptual DFT Framework

Methylmercury is an important environmental contaminant and its toxicity in vertebrates is associated with its interaction with selenium (e.g., selenol groups of selenoproteins or HSe^- the pivotal metabolite for selenium incorporation into selenoproteins). In a previous study, we demonstrated that diphenyl diselenide (PhSe)₂ decreased the deposition of Hg in mice treated with MeHg⁺. We hypothesized that (PhSe)₂ could be reduced metabolically to its selenol intermediate phenylselenol (PhSeH), which reacted with MeHg⁺ to form PhSeHgMe. To further support our hypothesis, in this work, we investigate the electronic chemical reactivity descriptors at ZORA-OPBE-D3(BJ)/ level of theory using the Fukui functions and the Dual descriptors. The results indicate that (PhSe)₂ and diphenyl disulfide (PhS)₂ (f+ > f^- ) act as poor nucleophiles towards MeHg⁺ and thus cannot be the detoxificant agent. As further proof, the reaction between diphenyl diselenide and MeHgCl was followed via UV-vis spectrophotometry and the spectra of the relevant species were computed using time-dependent density functional theory (TD-DFT) (CPCM-ZORA-CAM-B3LYP/ZORA-def2-TZVP). The large aromatic system in (PhSe)₂ ensures the delocalization of electrons and directly influences the HOMO-LUMO gap (HLG) (3.34 eV) < HLG of PhSeH (3.99 eV). A similar trend was observed with HLG (2.65 eV) for (PhS)₂ and 4.13 eV for PhSH. This selenol intermediate is the active reactant, experimentally generated from the reduction of (PhSe)₂ by NaBH₄, which in presence of MeHgCl forms methylmercury phenylselenide complex (PhSeHgMe), i.e. a non-toxic metabolite of methylmercury formed after administration of (PhSe)₂ to mice.