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