Harmon M A, Boehm M F, Heyman R A, Mangelsdorf D J
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75235-9050, USA.
Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):6157-60. doi: 10.1073/pnas.92.13.6157.
We report that methoprene and its derivatives can stimulate gene transcription in vertebrates by acting through the retinoic acid-responsive transcription factors, the retinoid X receptors (RXRs). Methoprene is an insect growth regulator in domestic and agricultural use as a pesticide. At least one metabolite of methoprene, methoprene acid, directly binds to RXR and is a transcriptional activator in both insect and mammalian cells. Unlike the endogenous RXR ligand, 9-cis-retinoic acid, this activity is RXR-specific; the methoprene derivatives do not activate the retinoic acid receptor pathway. Methoprene is a juvenile hormone analog that acts to retain juvenile characteristics during insect growth, preventing metamorphosis into an adult, and it has been shown to have ovicidal properties in some insects. Thus, a pesticide that mimics the action of juvenile hormone in insects can also activate a mammalian retinoid-responsive pathway. This finding provides a basis through which the potential bioactivity of substances exposed to the environment may be reexamined and points the way for discovery of new receptor ligands in both insects and vertebrates.
我们报告称，烯虫酯及其衍生物可通过视黄酸反应性转录因子——类视黄醇X受体（RXRs）发挥作用，从而刺激脊椎动物的基因转录。烯虫酯是一种用于家庭和农业的杀虫剂，作为昆虫生长调节剂。烯虫酯的至少一种代谢产物——烯虫酯酸，可直接与RXR结合，并且在昆虫和哺乳动物细胞中均为转录激活剂。与内源性RXR配体9-顺式视黄酸不同，这种活性具有RXR特异性；烯虫酯衍生物不会激活视黄酸受体途径。烯虫酯是一种保幼激素类似物，其作用是在昆虫生长过程中保留幼虫特征，防止变态为成虫，并且已证明它在某些昆虫中具有杀卵特性。因此，一种模拟昆虫保幼激素作用的杀虫剂也能激活哺乳动物类视黄醇反应途径。这一发现为重新审视暴露于环境中的物质的潜在生物活性提供了基础，并为在昆虫和脊椎动物中发现新的受体配体指明了方向。
