Inhibition of CYP19A1 aromatase and suppression of estradiol production by polyhalogenated carbazoles: an in vitro and in silico study.

Abstract

Polyhalogenated carbazoles (PHCZs) are emerging contaminants with largely unknown endocrine-disrupting effects. We evaluated 11 PHCZs against human and rat CYP19A1 via enzymatic, cellular, and computational assays. Three compounds (136-BCZ, 1-B-36-CCZ, 36-ICZ) inhibited human CYP19A1 with IC50 of 20.6, 18.1, and 4.7 μM (rat: 32.6, 28.3, 7.5 μM). Kinetic analyses showed mixed inhibition with Ki values of 24.29, 20.4, and 4.0 μM for human CYP19A1, indicating binding to both free enzyme and enzyme-substrate complex. Docking and 200 ns MD simulations revealed stable anchoring in the catalytic pocket via halogen-mediated hydrophobic interactions with Ile305, Val370, Met374, consistent with the strongest inhibitory activity of 36-ICZ due to iodine polarizability. Cellular assays in BeWo cells confirmed concentration-dependent estradiol suppression (5-20 μM) by all three. Network toxicology identified CYP19A1 as a central node linking PHCZs to polycystic ovary syndrome and osteoporosis; bivariate correlation and 3D-QSAR modeling further revealed logP and pKa as key determinants of activity. Collectively, this study provides the first direct mechanistic evidence that PHCZs inhibit CYP19A1, revealing a specific endocrine-disrupting pathway with reproductive health implications and a framework for risk assessment and safer design.

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