TY - JOUR
T1 - Effects of antihistamines on the H295R steroidogenesis - Autocrine up-regulation following 3β-HSD inhibition
AU - Munkboel, Cecilie Hurup
AU - Hasselstrøm, Stine Bjerregaard
AU - Kristensen, David Møbjerg
AU - Styrishave, Bjarne
N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.
PY - 2018
Y1 - 2018
N2 - Millions of people of all ages suffer from allergies worldwide and as a consequence antihistamines are among the most commonly prescribed pharmaceuticals in the world. We investigated the disruptive effects of three antihistamines, promethazine (PMZ), cetirizine (CET) and fexofenadine (FEX) on the H295R steroidogenesis. A multi-steroid LC-MS/MS method was used to quantify 13 steroid hormones in the steroidogenesis. In addition, real-time RT-PCR was used to determine if exposure to antihistamines altered gene expression in the cell line. When exposing the H295R cells to PMZ and CET, significant increases in Δ5-steroids and significant decreases in Δ4-steroids were observed, indicating an inhibition of 3β-hydroxysteroid dehydrogenase (3β-HSD). A sequential decrease in corticosteroids, androgens and estrogens were also observed. Overall, FEX had no effect on the steroidogenesis even though minor effects were observed at the highest concentrations. Real-time RT-PCR showed that PMZ resulted in significant up-regulation of 3β-HSD and 17β-HSD, whereas CET only resulted in up-regulation of 3β-HSD. This indicated that the decrease in steroids downstream from 3β-HSD following PMZ and CT exposure induced a compensatory autocrine response in 3β-HSD gene expression. The effects on the steroidogenesis were observed at concentrations 30-50 times higher than the therapeutic plasma concentrations. However, antihistamines are lipophilic and may accumulate in adrenals and gonads. Thus, disruptive effects of PMZ and CET on human steroidogenesis cannot be excluded.
AB - Millions of people of all ages suffer from allergies worldwide and as a consequence antihistamines are among the most commonly prescribed pharmaceuticals in the world. We investigated the disruptive effects of three antihistamines, promethazine (PMZ), cetirizine (CET) and fexofenadine (FEX) on the H295R steroidogenesis. A multi-steroid LC-MS/MS method was used to quantify 13 steroid hormones in the steroidogenesis. In addition, real-time RT-PCR was used to determine if exposure to antihistamines altered gene expression in the cell line. When exposing the H295R cells to PMZ and CET, significant increases in Δ5-steroids and significant decreases in Δ4-steroids were observed, indicating an inhibition of 3β-hydroxysteroid dehydrogenase (3β-HSD). A sequential decrease in corticosteroids, androgens and estrogens were also observed. Overall, FEX had no effect on the steroidogenesis even though minor effects were observed at the highest concentrations. Real-time RT-PCR showed that PMZ resulted in significant up-regulation of 3β-HSD and 17β-HSD, whereas CET only resulted in up-regulation of 3β-HSD. This indicated that the decrease in steroids downstream from 3β-HSD following PMZ and CT exposure induced a compensatory autocrine response in 3β-HSD gene expression. The effects on the steroidogenesis were observed at concentrations 30-50 times higher than the therapeutic plasma concentrations. However, antihistamines are lipophilic and may accumulate in adrenals and gonads. Thus, disruptive effects of PMZ and CET on human steroidogenesis cannot be excluded.
KW - 3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors
KW - Autocrine Communication/drug effects
KW - Cell Line
KW - Cell Survival/drug effects
KW - Cetirizine/pharmacology
KW - Enzyme Inhibitors/pharmacology
KW - Gene Expression Regulation/drug effects
KW - Histamine Antagonists/pharmacology
KW - Histamine H1 Antagonists/pharmacology
KW - Humans
KW - Promethazine/pharmacology
KW - Real-Time Polymerase Chain Reaction
KW - Steroids/biosynthesis
KW - Terfenadine/analogs & derivatives
KW - Up-Regulation/drug effects
U2 - 10.1016/j.tiv.2018.01.026
DO - 10.1016/j.tiv.2018.01.026
M3 - Journal article
C2 - 29409762
SN - 0887-2333
VL - 48
SP - 302
EP - 309
JO - Toxicology in vitro : an international journal published in association with BIBRA
JF - Toxicology in vitro : an international journal published in association with BIBRA
ER -