Halogenated phenolic disinfectants suppress 11β-hydroxysteroid dehydrogenase 2 activity in human and rat models:...

Halogenated phenolic disinfectants (HDs) are widely used in industrial and personal care products. However, whether these HDs inhibit human and rat 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity to interfere with glucocorticoid metabolism remains unclear. Michaelis-Menten kinetics showed high 11β-HSD2 activity (human placenta: Km, 46.0 nM, Vmax, 48.21pmol/mg/min; rat kidney: Km, 50.01 nM, Vmax, 70.6pmol/mg/min). Screening at 100 µM revealed significant inhibition by most HDs (residual activity <50%), except triclocarban and trichloroacetone. Dose-response assays identified hexachlorophene as the most potent inhibitor (human IC₅₀, 3.83 µM; rat IC₅₀, 1.48 µM). The binding affinities of hexachlorophene and dichlorophene were assessed using Surface Plasmon Resonance, showing KDs of 10.60 and 48.50 μM, respectively. Enzyme kinetics and Lineweaver-Burk plots demonstrated mixed inhibition by HDs, suggesting dual interference with substrate binding and NAD⁺ binding. In human BeWo trophoblast cells, HDs differentially suppressed cortisone formation, with dichlorophene, bromochlorophene, and fenticlor showing inhibition even at 1 µM. Molecular docking revealed HDs binding to NAD⁺ and cortisol binding sites in human 11β-HSD2, with hexachlorophene forming hydrogen bonds with catalytic residues (Ser219, Tyr232). Structure-activity relationship (SAR) and 3D-QSAR analyses highlighted inverse correlations between inhibitory potency and LogP/molecular volume (r = 0.9214 for pharmacophore). ADMET (absorption, distribution, metabolism, elimination, and toxicity) profiling indicated poor solubility, high plasma protein binding, and potential hepatotoxicity. Network toxicology analysis for hypertensive disorders of pregnancy (including gestational hypertension and preeclampsia), now supported by cellular bioassay data, implicates this dysregulated pathway in the potential pathogenesis of HD-induced disorders. These findings elucidate HDs as potent, species-conserved 11β-HSD2 inhibitors with mixed mechanisms, underscoring their endocrine-disrupting potential and structure-dependent bioactivity.