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Industrial phenolic compounds targeting 11β-hydroxysteroid dehydrogenase 2: A comparative in silico and
Lubin Xie1, Lei Shi2, Yunbing Tang3
1Department of Urology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Department of Obstetrics and Gynecology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Abstract:
Industrial phenolic compounds (IPCs) are widespread environmental contaminants with known endocrine-disrupting potential. This study aimed to investigate the inhibition of 13 IPCs on human and rat 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), a crucial enzyme responsible for cortisol inactivation. The inhibitory potential of IPCs was evaluated using enzymatic screening. Direct enzyme binding was assessed via surface plasmon resonance (SPR). Intracellular cortisol-to-cortisone conversion was tested in human placental BeWo cells. Additionally, structure-activity relationships, 3D-QSAR analyses, molecular docking were conducted, followed by integrated network toxicology to identify affected biological pathways. Screening identified four active inhibitors of the human 11β-HSD2: 2-bromophenol, 4-nonylphenol, 4-dodecylphenol (the most potent, IC50 = 3.50 µM), and pentabromophenol (IC50 = 4.96 µM). In BeWo cells, 4-dodecylphenol and pentabromophenol successfully inhibited cellular cortisol-to-cortisone conversion without inducing cytotoxicity, with pentabromophenol demonstrating activity at concentrations as low as 1 µM. SPR confirmed the direct and reversible binding of 4-dodecylphenol to human 11β-HSD2 with a KD of 1.84 µM. Inhibition modeling revealed a structure-dependent dichotomy: alkylphenols (4-nonylphenol and 4-dodecylphenol) functioned predominantly as competitive inhibitors, whereas brominated phenols (2-bromophenol and pentabromophenol) exhibited mixed/noncompetitive inhibition. Furthermore, 3D-QSAR identified lipophilicity and hydrophobic interactions as the primary determinants of inhibitory potency. Rat 11β-HSD2 was markedly less sensitive to these compounds, demonstrating a ∼43-fold lower potency for 4-dodecylphenol than human enzyme. Integrated network toxicology suggested candidate placental pathways potentially related to preeclampsia, including steroid hormone biosynthesis. In conclusion, specific IPCs act as potent, species-selective inhibitors of human 11β-HSD2 that may disrupt placental glucocorticoid metabolism.
Insights
Industrial phenolic compounds (IPCs) inhibit human 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), an enzyme crucial for cortisol metabolism. This endocrine disruption may impact placental function and potentially lead to conditions like preeclampsia.
Area of Science:
- Environmental Toxicology
- Endocrinology
- Biochemistry
Background:
- Industrial phenolic compounds (IPCs) are prevalent environmental contaminants.
- Many IPCs possess endocrine-disrupting capabilities.
- 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) is vital for inactivating cortisol, particularly in placental tissues.
Purpose of the Study:
- To investigate the inhibitory effects of 13 IPCs on human and rat 11β-HSD2.
- To elucidate the mechanisms of inhibition and structure-activity relationships.
- To assess the potential impact on placental glucocorticoid metabolism and related pathways.
Main Methods:
- Enzymatic screening and surface plasmon resonance (SPR) for enzyme inhibition and binding.
- Cell-based assays using human placental BeWo cells to assess cortisol-to-cortisone conversion.
- Structure-activity relationship (SAR) studies, 3D-QSAR, molecular docking, and network toxicology.
Main Results:
- Four IPCs inhibited human 11β-HSD2, with 4-dodecylphenol (IC50 = 3.50 µM) and pentabromophenol (IC50 = 4.96 µM) being the most potent.
- 4-dodecylphenol and pentabromophenol inhibited cellular cortisol conversion in BeWo cells without cytotoxicity.
- Inhibition mechanisms varied by chemical structure (competitive for alkylphenols, mixed/noncompetitive for brominated phenols); lipophilicity was key.
- Human 11β-HSD2 was significantly more sensitive to inhibition than the rat enzyme.
- Network toxicology suggested links to preeclampsia pathways, including steroid hormone biosynthesis.
Conclusions:
- Specific IPCs are potent, species-selective inhibitors of human 11β-HSD2.
- These compounds can disrupt placental glucocorticoid metabolism.
- Potential implications for endocrine disruption and adverse pregnancy outcomes, such as preeclampsia, warrant further investigation.
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