Structural determinants of paraben-mediated 11β-hydroxysteroid dehydrogenase 1 inhibition: Integrated mechanistic, kinetic and in silico approaches to cortisol metabolism

Parabens are extensively employed as antimicrobial preservatives in cosmetics, personal care items, and pharmaceuticals. However, their potential metabolism regulating effects, particularly regarding the inhibition of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), remains unknown. This study assessed 4-hydroxybenzoic acid and 9 parabens for their ability to inhibit human and rat liver 11β-HSD1, investigating their mechanism of action, structure-activity relationship (SAR), molecular interactions (via in silico docking), and influence on cortisol metabolism in LX-2 cells. Nonylparaben emerged as the most potent inhibitor, demonstrating the lowest IC 50 values (human: 6.29 μM) and strongest binding affinity (ΔG: human: −6.84 kcal/mol). The inhibitor trend followed nonyl > heptyl (IC 50  = 11.37 μM) > hexyl (15.32 μM) > benzyl (29.99 μM) > phenyl (53.27 μM) > butyl (58.87 μM) paraben. Short-chain parabens (