Abstract
Examination of three retinoid X receptor (RXR) agonists [Targretin (TRG), UAB30, and 4-methyl-UAB30 (4-Me-UAB30)] showed that all inhibited mammary cancer in rodents and two (TRG and 4-Me-UAB30) strikingly increased serum triglyceride levels. Agents were administered in diets to female Sprague-Dawley rats. Liver RNA was isolated and microarrayed on the Affymetrix GeneChip Rat Exon 1.0 ST array. Statistical tests identified genes that exhibited differential expression and fell into groups, or modules, with differential expression among agonists. Genes in specific modules were changed by one, two, or all three agonists. An interactome analysis assessed the effects on genes that heterodimerize with known nuclear receptors. For proliferator-activated receptor α/RXR-activated genes, the strongest response was TRG > 4-Me-UAB30 > UAB30. Many liver X receptor/RXR-related genes (e.g., Scd-1 and Srebf1, which are associated with increased triglycerides) were highly expressed in TRG and 4-Me-UAB30- but not UAB30-treated livers. Minimal expression changes were associated with retinoic acid receptor or vitamin D receptor heterodimers by any of the agonists. UAB30 unexpectedly and uniquely activated genes associated with the aryl hydrocarbon hydroxylase (Ah) receptor (Cyp1a1, Cyp1a2, Cyp1b1, and Nqo1). Based on the Ah receptor activation, UAB30 was tested for its ability to prevent dimethylbenzanthracene (DMBA)-induced mammary cancers, presumably by inhibiting DMBA activation, and was highly effective. Gene expression changes were determined by reverse transcriptase-polymerase chain reaction in rat livers treated with Targretin for 2.3, 7, and 21 days. These showed similar gene expression changes at all three time points, arguing some steady-state effect. Different patterns of gene expression among the agonists provided insight into molecular differences and allowed one to predict certain physiologic consequences of agonist treatment.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
