Linking Copper Concentration to Oxidative Potential of PM _2.5 : Mechanistic Study of Glutathione Depletion in Surrogate Lung Fluid

Inhaled ambient fine particulate matter (PM2.5) can release toxic chemicals in the respiratory tract, with transition metals (TMs) such as copper (Cu), iron (Fe), and manganese (Mn) playing a key role in generating oxidative potential (OP) through antioxidant depletion and reactive oxygen species formation. As glutathione (GSH) is an essential antioxidant in the human body, it is commonly used in acellular assays to estimate OP. Previous empirical models relating TM concentrations to GSH-based OP (OPGSH) lack mechanistic explanation. Here, we systematically investigated GSH depletion by Cu, Fe, and Mn in an acellular surrogate lung fluid. Our results demonstrate that Cu is the primary driver of GSH oxidation, whereas Fe and Mn have minimal effects. Kinetic analyses reveal that GSH depletion follows a Michaelis–Menten-like dependence on the Cu concentration and a pseudo-second-order relationship with the GSH concentration. Based on these findings, we propose a quasi-Michaelis–Menten mechanism for Cu-catalyzed GSH oxidation. We further revealed suppressing effects between Cu and coexisting organics in ambient PM on GSH depletion. This mechanistic framework quantitatively links the Cu concentration to OPGSH, providing a foundation for more accurate OP modeling based on PM2.5 composition and advancing our understanding of oxidative stress pathways in the human respiratory system.