Assessment of the analgesic dipyrone as a possible (anti)androgenic endocrine disruptor

• Published in: Toxicology letters 2018-03, Vol.285, p.139-147
• Main Authors: Passoni, Marcella Tapias, Kristensen, Maja Nørgaard, Morais, Rosana Nogueira, Woitkowiak, Claudia, Boareto, Ana Claudia, da Silva Amaral, Bruna Andreotti, Grechi, Nicole, Dalsenter, Paulo Roberto, Munkboel, Cecilie Hurup, Styrishave, Bjarne, Kristensen, David Møbjerg, Gomes, Caroline, van Ravenzwaay, Bennard, Martino-Andrade, Anderson Joel
• Format: Article
• Language: English
• Subjects: Analgesics - blood; Analgesics - toxicity; Androgen Receptor Antagonists - blood; Androgen Receptor Antagonists - toxicity; Androgens - blood; Androgens - toxicity; Animals; Biological Assay; Cell Line, Tumor; Dipyrone - blood; Dipyrone - toxicity; Endocrine Disruptors - blood; Endocrine Disruptors - toxicity; Female; Fetal rat testosterone production; H295R steroidogenesis assay; Hershberger assay; Humans; Male; Metamizole; Pregnancy; Prenatal Exposure Delayed Effects - blood; Prenatal Exposure Delayed Effects - chemically induced; Rats; Rats, Wistar; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Testis - drug effects; Testis - embryology; Testis - metabolism; Testosterone - biosynthesis; Yeast androgen screen
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2017.12.021

•Dipyrone and its metabolites inhibit steroidogenesis in H295R cell line.•Maternal exposure to dipyrone does not affect ex vivo testosterone production in rats.•Dipyrone and its metabolites do not elicit androgen agonistic/antagonistic activities. Mild analgesics have been associated with antiandrogenic effects, but there are no such studies on dipyrone, despite its high prevalence of use in many countries. We examined the production of steroid hormones in human H295R cells after exposure to dipyrone and two metabolites, 4-Methylaminoantipyrine (MAA) and 4-Aminoantipyrine (AA), as well as fetal testicular testosterone production in rats following maternal dipyrone exposure. Androgen agonistic/antagonistic effects were examined in vitro for dipyrone and its metabolites in the Yeast Androgen Screen (YAS) assay and in vivo for dipyrone through the Hershberger assay. In vitro we tested dipyrone, MAA, and AA (0.1–1000 μM) while in vivo we used dipyrone (50, 100, 200 mg/kg/day). In the H295R assay, dipyrone, MAA and AA reduced the production of androgens and corticosteroids. Testosterone was reduced at concentrations 4–13 times higher than the maximum plasma concentrations reported in humans for MAA and AA. No effects were observed in the fetal testosterone production assay. In the YAS and Hershberger assays, no androgen agonistic/antagonistic activities were observed. These results indicate that dipyrone and its metabolites do not interact with the androgen receptor, but have the potential to inhibit steroidogenesis, however only at concentrations that are not relevant under normal medical use.