Structural and mechanistic insights into industrial phenolic compounds as potent inhibitors of human and rat 5α-reductase 1

This study identifies environmental chemicals 4-nonylphenol, 4-dodecylphenol, pentabromophenol, and popular anesthetics drug propofol as moderate to potent inhibitors of human and rat 5α-reductase type 1 (5α-R1), revealing novel endocrine-disrupting mechanisms in human brain cell and rat brain microsomes. Pentabromophenol exhibited the highest potency (IC₅₀ = 1.71 µM for human 5α-R1) with mixed/noncompetitive inhibition, supported by Surface Plasmon Resonance binding ( KD = 1.22 µM). A 3D-QSAR pharmacophore model (Hypo1) highlighted critical structural features, including a hydrogen-bond acceptor and hydrophobic interactions, explaining pentabromophenol efficacy. Species differences emerged, with human 5α-R1 showing high pentabromophenol binding affinity (-6.80 kcal/mol via halogen bonds with Arg176). Inhibition may reduce neurosteroids (e.g., allopregnanolone) and androgens (e.g., dihydrotestosterone). These findings underscore industrial phenolic compound capacity to dysregulate neurosteroid homeostasis in a structure- and species-dependent manner, highlighting their endocrine-disrupting risks. • Phenolic compounds inhibit human and rat 5α-R1. • Phenolic compounds bind to 5α-R1 NADPH-binding sites as mixed inhibitors. • SPR shows high affinity of pentabromophenol with human 5α-R1.