Steroidogenic disruptive effects of the serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol in the H295R cell assay and in a recombinant CYP17 assay

Toxicology in Vitro : an International Journal Published in Association with BIBRA
Julie IslinBjarne Styrishave

Abstract

The aim of this study was to determine the steroidogenic endocrine disrupting effect of three widely used serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol, using two in vitro models, the H295R assay and a recombinant CYP17 enzyme assay. Steroid hormones were quantified using LC-MS/MS. Duloxetine showed endocrine disrupting effects at 5-20μM with CYP17 being the main target. Venlafaxine also affected the steroidogenesis, mainly by affecting the CYP17 lyase reaction, although at much higher concentrations i.e. 100μM. Tramadol only exerted minor effects on the steroidogenesis with the lowest observed effect at 314μM. Based on the H295R results, the inhibition of CYP17 by duloxetine and venlafaxine was investigated in a recombinant CYP17 assay with the use of the 4 major CYP17 substrates pregnenolone, progesterone, 17α-hydroxypregnenolone and 17α-hydroxyprogesterone. Both duloxetine and venlafaxine inhibited CYP17 enzyme activity, but duloxetine was most potent. IC50-values were in the range 5.3-21μM for duloxetine and 1318-2750μM for venlafaxine. Overall, results from the recombinant CYP17 assay confirmed the results from the H295R cell assay. Using testosterone as end point, the margin of safety (d...Continue Reading

Citations

Feb 20, 2020·Journal of Applied Toxicology : JAT·Patrícia Villela E SilvaWilma De Grava Kempinas
May 3, 2018·Biology of Reproduction·Cecilie Hurup MunkboelBjarne Styrishave
Mar 8, 2021·European Journal of Pharmacology·Pavlina PavlidiChristina Dalla
Sep 30, 2020·The Journal of Steroid Biochemistry and Molecular Biology·Malene Louise JohannsenBjarne Styrishave
May 24, 2021·BMC Women's Health·Rong LeiZhenjian Yu

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