Paraben Preservatives Exhibit Inhibition on Human and Rat Steroid 5α-Reductase 1: A Comprehensive 3D-QSAR and Computational Analysis

Parabens are preservatives used in personal care products, cosmetics, and pharmaceuticals. Steroid 5α-reductase 1 (SRD5A1) catalyzes the conversion of testosterone to dihydrotestosterone and is present in the brain, contributing to neurosteroid production. This study aimed to assess the effects of nine paraben preservatives on SRD5A1 in human SF126 glioblastoma cell and rat brain microsomes, particularly focusing on dihydrotestosterone production in SF126 cells. The results showed that methyl, ethyl, propyl, butyl, hexyl, heptyl, nonyl, phenyl, and benzyl paraben inhibited human SRD5A1, with nonylparaben having the strongest effect (7.59 μM). Additionally, kinetic analysis indicated that parabens acted as mixed/noncompetitive inhibitors, leading to a significant decrease in dihydrotestosterone production in SF126 cells. While rat SRD5A1 exhibited lower sensitivity to parabens, docking analysis revealed that parabens bind to the NADPH-binding site of both human and rat SRD5A1. In conclusion, these results highlight the inhibitory effects of paraben preservatives on SRD5A1 and elucidate their binding mechanisms, underscoring their role in hormone production.