Inhibition of human and rat 11β-hydroxysteroid dehydrogenase 2 by parabens: Mechanistic insights into cortisol metabolism disruption and structure-activity relationship and in silico docking

Parabens are widely used as antimicrobial preservatives in cosmetics, personal care products, and pharmaceuticals. However, their endocrine-disrupting potential, particularly their impact on 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), remains unclear. This study evaluated 9 parabens for their inhibitory potency against human placental and rat renal 11β-HSD2, mode of action, structure-activity relationship (SAR), molecular interactions (via in silico docking) and surface plasmon resonance (SPR) binding analysis, and effects on HSD11B2 expression and cortisol metabolism in human placental BeWo cells. Nonyl paraben was the most potent inhibitor in both species, with the lowest IC₅₀ (human: 15.24 μM, rat: 10.79 μM) and strongest binding affinity (KD: human 3.38 × 10^-5 M; ΔG: human: -6.43 kcal/mol, rat: -6.37 kcal/mol). Short-chain parabens (+ cofactor site in humans and rats. SAR analysis identified lipophilicity and molecular weight as key determinants of inhibitory strength, with higher values correlating with greater potency. A 3D-QSAR pharmacophore model confirmed hydrophobic interactions as essential for inhibition. Species-specific differences in binding mechanisms highlight the need for caution when extrapolating animal data to humans. These results provide critical insights into the endocrine-disrupting effects of parabens, emphasizing their potential to interfere with cortisol homeostasis in a structure and species-dependent manner.