title: Effects on gene expression in rat liver after administration of RXR agonists: UAB30, 4-methyl-UAB30, and Targretin (Bexarotene).
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.
authors.affiliation: Medical College of Wisconsin, Cancer Center, Department of Pharmacology Toxicology, Milwaukee, Wisconsin, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Vedell
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Clinton J
authors.initials: CJ
authors.lastname: Grubbs
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Yin
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.forename: Kirby I
authors.initials: KI
authors.lastname: Bland
authors.forename: Donald D
authors.initials: DD
authors.lastname: Muccio
authors.forename: Dusica
authors.initials: D
authors.lastname: Cvetkovic
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.forename: Ronald
authors.initials: R
authors.lastname: Lubet
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D000077610:Bexarotene; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: D005231:Fatty Acids, Unsaturated; D009281:Naphthalenes; D047492:Peroxisome Proliferator-Activated Receptors; D018336:Receptors, Aryl Hydrocarbon; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014280:Triglycerides; D015127:9,10-Dimethyl-1,2-benzanthracene; D019324:beta-Naphthoflavone; D000077610:Bexarotene; D001189:Aryl Hydrocarbon Hydroxylases; C112106:UAB 30