title: Valproic acid and its derivatives enhanced estrogenic activity but not androgenic activity in a structure dependent manner.
abstract: Steroid hormones affect metabolic pathways and cellular functions. Valproic acid (VPA), used as antiepileptic drug, inhibits histone deacetylases and interacts with intracellular receptors. We analyzed the impact of VPA and VPA derivatives on activation of estrogen and androgen receptors (ER and AR) using reporter gene assays. VPA and its long-chain derivatives 2-(2-propynyl)-hexanoic acid [butyl-4-yn-VPA], 2-(2-propynyl)-heptanoic acid [S-pentyl-4-yn-VPA] and 2-(2-propynyl)-nonanoic acid [heptyl-4-yn-VPA] enhanced 17β-estradiol-induced ERα and ERβ activation partly synergistically with a structure-activity correlation. The extent of this effect regarding to ERα activation increased with prolongation of the aliphatic side chain. Regarding AR activation, VPA, S-pentyl-4-yn- and heptyl-4-yn-VPA slightly induced AR activity when tested alone. In combination with the AR agonist 5α-dihydrotestosterone, VPA, S-pentyl-4-yn- and heptyl-4-yn-VPA showed anti-androgenic effects without an apparent structural relation. Our results indicate that VPA and its derivatives affect estrogen signaling with a structural specificity, while the (anti-)androgenic effects of these compounds are not structurally correlated.
authors.affiliation: BfR - Federal Institute for Risk Assessment, Department of Food Safety, Berlin, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Stempin
authors.forename: Susanne
authors.initials: S
authors.lastname: Andres
authors.forename: Maja
authors.initials: M
authors.lastname: Bumke Scheer
authors.forename: Ariane
authors.initials: A
authors.lastname: Rode
authors.forename: Heinz
authors.initials: H
authors.lastname: Nau
authors.forename: Albrecht
authors.initials: A
authors.lastname: Seidel
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lampen
mesh_terms: D000726:Androgen Antagonists / Q000633:toxicity*; D000927:Anticonvulsants / Q000633:toxicity*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000633:toxicity*; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000633:toxicity*
chemical_list: D000726:Androgen Antagonists; D000927:Anticonvulsants; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011944:Receptors, Androgen; D014635:Valproic Acid; D008156:Luciferases
keywords: 17β-estradiol; 2-(2-propynyl)-heptanoic acid; 2-(2-propynyl)-hexanoic acid; 2-(2-propynyl)-nonanoic acid; 2-ethyl-4-pentynoic acid; 2-n-propyl-2-pentenoic acid; 5α-dihydrotestosterone; AP-1; AR; Androgen receptor (AR); DHT; E(2); E-2-en-VPA; ER; ERα; ERβ; Estrogen receptor (ER); HDAC; HEK293; Human Embryonic Kidney 293 cells; Luciferase reporter gene assay; S-pentyl-4-yn-VPA; Teratogenicity; VPA; VPA derivatives; Valproic acid (VPA); activator protein 1; androgen receptor; butyl-4-yn-VPA; estrogen receptor; ethyl-4-yn-VPA; heptyl-4-yn-VPA; histone deacetylase; valproic acid (2-propylpentanoic acid)