Endocrine-Disrupting\nEffects of Salicylate Preservatives\non Neurosteroidogenesis: Targeting 5α-Reductase Type 1

Salicylate preservatives are widely used in consumer\nproducts and\npharmaceuticals. This study investigates their potential endocrine-disrupting\neffects on neurosteroidogenesis, focusing on 5α-reductase type\n1 (SRD5A1). We evaluated the effects of 13 salicylates on human SRD5A1\nusing SF126 glioblastoma cell microsomes and rat brain microsomes,\nexamining dihydrotestosterone production in SF126 cells. Results revealed\na hierarchy of inhibitory potency against human SRD5A1, with methyl\nsalicylate (IC<sub>50</sub>, 71.93 μM) to menthyl salicylate\n(2.41 μM), indicating increasing potency. Kinetic analysis indicates\ntheir mixed/noncompetitive inhibitions. In SF126 cells, all salicylates\nat 100 μM significantly reduced dihydrotestosterone production.\nRat SRD5A1 showed reduced sensitivity, with menthyl salicylate as\nthe most potent inhibitor (IC<sub>50</sub>, 17.12 μM). Docking\nanalysis suggests salicylates bind to the reduced nicotinamide adenine\ndinucleotide phosphate site of both human and rat SRD5A1. Bivariate\ncorrelation analysis highlights the influence of LogP, molecular weight,\ncarbon number in the alcohol moiety, and p<i>K</i><sub>a</sub> on inhibitory potency. 3D-QSAR revealed the importance of hydrophobic\naromatic regions in SRD5A1 binding. This study delineates the inhibitory\neffects of salicylates and binding mechanisms on human and rat SRD5A1,\nproviding insights into their impact on neurosteroid production.