Effects of antihistamines on the H295R steroidogenesis - Autocrine up-regulation following 3β-HSD inhibition

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.