Structural Determinants of Phthalate Toxicity: Contrasting Mechanisms of DMP and DBP Binding to Human Serum Albumin.

Abstract

The widespread environmental presence of phthalate plasticizers, such as dimethyl phthalate (DMP) and dibutyl phthalate (DBP), raises significant concerns due to their endocrine-disrupting potential. Understanding their interaction with human serum albumin (HSA), the primary transport protein in blood, is critical for predicting their systemic distribution and toxicity. Herein, we present a comparative investigation into the interaction mechanisms of DMP and DBP with HSA by integrating multispectral analyses with molecular docking. UV-Vis and inner-filter-corrected fluorescence spectroscopy suggest that both compounds quench HSA fluorescence via a combined (mixed dynamic and static) quenching mechanism accompanied by endothermic, entropy-driven interactions (ΔH > 0, ΔS > 0), with DMP inducing stronger quenching of the Trp-214 microenvironment. Synchronous fluorescence indicates that DMP is associated with a polarity increase around aromatic residues (Trp/Tyr), whereas DBP causes minimal local polarity perturbation. Strikingly, resonance light scattering (RLS) suggests opposing effects on protein assembly: DMP suppresses HSA self-association, whereas DBP promotes significant protein aggregation. Molecular docking simulations provide structural models consistent with these spectroscopic observations, suggesting that DMP may preferentially interact within Sudlow's site I in subdomain IIA, adjacent to Trp-214, whereas the bulkier DBP molecule may favor Sudlow's site II in subdomain IIIA primarily through hydrophobic interactions, which is consistent with partial unfolding and aggregation. These findings suggest how differences in alkyl chain length between phthalates may influence their interaction modes and macroscopic protein assembly, offering mechanistic insights for assessing the health risks of phthalates.

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