title: Effects of methoprene, its metabolites, and breakdown products on retinoid-activated pathways in transfected cell lines.
abstract: Methoprene (isopropyl (2E,4E)-11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate) is an insect juvenile hormone agonist that blocks metamorphosis in some insects. Recent evidence suggests that a metabolite, methoprene acid, activates vertebrate retinoid X receptors (RXRs), and may interfere with retinoic acid-regulated developmental processes. Methoprene, methoxy-methoprene acid, and two major breakdown products were tested for their ability to interfere with retinoid-regulated pathways when using transfected cells. The CV-1 cells were transiently transfected with genes encoding RXRs and response elements attached to luciferase reporters, and retinoic acid-sensitive F9 cells were stably transfected with retinoic acid receptor (RAR)/RXR response elements attached a lacZ reporter (Sil-REM/beta-gal-NEO). Experiments confirmed that methoxy-methoprene acid acted as a ligand for RXRs and was capable of activating transcription through RAR/RXR response elements. However, neither methoprene nor the breakdown products, 7-methoxycitronellal and 7-methoxycitronellic acid, activated transcription in transfected CV-1 or F9 cells. Methoprene and methoxy-methoprene acid may interfere with the conversion of all-trans-retinol and all-trans-retinaldehyde to all-trans-retinoic acid in the F9-derived cell line. Methoprene was as effective as the retinol dehydrogenase inhibitor citral in blocking the retinol-induced transcription of RAR/RXR-regulated reporter genes, whereas methoxy-methoprene acid blocked transcription stimulated by retinaldehyde.
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Boulevard, Duluth, Minnesota 55804, USA. pschoff@nrri.umn.edu
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Schoff
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Ankley
mesh_terms: D000080462:Acyclic Monoterpenes; D000818:Animals; D002460:Cell Line; D000882:Haplorhini; D007605:Juvenile Hormones / Q000378:metabolism / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008675:Metamorphosis, Biological / Q000187:drug effects; D008726:Methoprene / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D039821:Monoterpenes / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism; D012176:Retinoids / Q000145:classification / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D001616:beta-Galactosidase / Q000187:drug effects / Q000378:metabolism
chemical_list: D000080462:Acyclic Monoterpenes; D007605:Juvenile Hormones; D039821:Monoterpenes; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D008726:Methoprene; D008156:Luciferases; D001616:beta-Galactosidase; C007076:citral