Industrial phenolic compounds targeting 11β-hydroxysteroid dehydrogenase 2: A comparative in silico and structure-activity investigation in humans and rats.

Industrial phenolic compounds (IPCs) are widespread environmental contaminants with known endocrine-disrupting potential. This study aimed to investigate the inhibition of 13 IPCs on human and rat 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), a crucial enzyme responsible for cortisol inactivation. The inhibitory potential of IPCs was evaluated using enzymatic screening. Direct enzyme binding was assessed via surface plasmon resonance (SPR). Intracellular cortisol-to-cortisone conversion was tested in human placental BeWo cells. Additionally, structure-activity relationships, 3D-QSAR analyses, molecular docking were conducted, followed by integrated network toxicology to identify affected biological pathways. Screening identified four active inhibitors of the human 11β-HSD2: 2-bromophenol, 4-nonylphenol, 4-dodecylphenol (the most potent, IC50 = 3.50 µM), and pentabromophenol (IC50 = 4.96 µM). In BeWo cells, 4-dodecylphenol and pentabromophenol successfully inhibited cellular cortisol-to-cortisone conversion without inducing cytotoxicity, with pentabromophenol demonstrating activity at concentrations as low as 1 µM. SPR confirmed the direct and reversible binding of 4-dodecylphenol to human 11β-HSD2 with a KD of 1.84 µM. Inhibition modeling revealed a structure-dependent dichotomy: alkylphenols (4-nonylphenol and 4-dodecylphenol) functioned predominantly as competitive inhibitors, whereas brominated phenols (2-bromophenol and pentabromophenol) exhibited mixed/noncompetitive inhibition. Furthermore, 3D-QSAR identified lipophilicity and hydrophobic interactions as the primary determinants of inhibitory potency. Rat 11β-HSD2 was markedly less sensitive to these compounds, demonstrating a ∼43-fold lower potency for 4-dodecylphenol than human enzyme. Integrated network toxicology suggested candidate placental pathways potentially related to preeclampsia, including steroid hormone biosynthesis. In conclusion, specific IPCs act as potent, species-selective inhibitors of human 11β-HSD2 that may disrupt placental glucocorticoid metabolism.