Interference of Paraben Compounds with Estrogen Metabolism by Inhibition of 17β-Hydroxysteroid Dehydrogenases

Abstract

Parabens are effective preservatives widely used in cosmetic products and processed food, with high human exposure. Recent evidence suggests that parabens exert estrogenic effects. This work investigated the potential interference of parabens with the estrogen-activating enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) 1 and the estrogen-inactivating 17β-HSD2. A ligand-based 17β-HSD2 pharmacophore model was applied to screen a cosmetic chemicals database, followed by in vitro testing of selected paraben compounds for inhibition of 17β-HSD1 and 17β-HSD2 activities. All tested parabens and paraben-like compounds, except their common metabolite p-hydroxybenzoic acid, inhibited 17β-HSD2. Ethylparaben and ethyl vanillate inhibited 17β-HSD2 with IC50 values of 4.6 ± 0.8 and 1.3 ± 0.3 µM, respectively. Additionally, parabens size-dependently inhibited 17β-HSD1, whereby hexyl- and heptylparaben were most active with IC50 values of 2.6 ± 0.6 and 1.8 ± 0.3 µM. Low micromolar concentrations of hexyl- and heptylparaben decreased 17β-HSD1 activity, and ethylparaben and ethyl vanillate decreased 17β-HSD2 activity. However, regarding the very rapid metabolism of these compounds to the inactive p-hydroxybenzoic acid by esterases, it needs to be determined under which conditions low micromolar concentrations of these parabens or their mixtures can occur in target cells to effectively disturb estrogen effects in vivo.

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

“…Engeli et al addressed their potential interference with local estrogen metabolism by inhibiting 17β-HSD1 and 17β-HSD2 (Engeli et al 2017). All parabens under investigation moderately inhibited 17β-HSD2.…”

A Survey of Parabens in Commercial Baby Wipes From Brazil and Estimation of Daily Exposure

“…The rapid metabolism of parabens suggests that they are metabolized faster after the intake than by dermal absorption, thus explaining that topical use is the main source of exposure to parabens. [18][19][20][21] Parabens are rapidly absorbed through the gastrointestinal tract or, more slowly, through the skin because the latter mechanism depends on the action of carboxylesterase enzymes and subcutaneous fat that affect the dermal absorption. 22 After absorption or ingestion, metabolism and urinary excretion are influenced by the size of the paraben alkyl chain, giving them short half-lives in the human body, ranging from 22 minutes for methylparaben to 87 minutes for butylparaben.…”

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“…Parabens interferes with estrogen metabolism (inhibits 17β-HSD1 and 17β-HSD2), and cause skin reactions including, rash, contact dermatitis, urticaria, etc. 2,6 The use of benzoic acid and benzoates preservatives has been reviewed which may cause adverse side effects such as nonimmunological contact urticaria, convulsions, asthma, and metabolic acidosis, etc. 7 Official methods employed for assessment of the effectiveness of the preservative systems have been well described in different pharmacopeias such as British Pharmacopeia and the United States Pharmacopeia (USP).…”