title: Potential candidate genomic biomarkers of drug induced vascular injury in the rat.
abstract: Drug-induced vascular injury is frequently observed in rats but the relevance and translation to humans present a hurdle for drug development. Numerous structurally diverse pharmacologic agents have been shown to induce mesenteric arterial medial necrosis in rats, but no consistent biomarkers have been identified. To address this need, a novel strategy was developed in rats to identify genes associated with the development of drug-induced mesenteric arterial medial necrosis. Separate groups (n=6/group) of male rats were given 28 different toxicants (30 different treatments) for 1 or 4 days with each toxicant given at 3 different doses (low, mid and high) plus corresponding vehicle (912 total rats). Mesentery was collected, frozen and endothelial and vascular smooth muscle cells were microdissected from each artery. RNA was isolated, amplified and Affymetrix GeneChip® analysis was performed on selectively enriched samples and a novel panel of genes representing those which showed a dose responsive pattern for all treatments in which mesenteric arterial medial necrosis was histologically observed, was developed and verified in individual endothelial cell- and vascular smooth muscle cell-enriched samples. Data were confirmed in samples containing mesentery using quantitative real-time RT-PCR (TaqMan™) gene expression profiling. In addition, the performance of the panel was also confirmed using similarly collected samples obtained from a timecourse study in rats given a well established vascular toxicant (Fenoldopam). Although further validation is still required, a novel gene panel has been developed that represents a strategic opportunity that can potentially be used to help predict the occurrence of drug-induced mesenteric arterial medial necrosis in rats at an early stage in drug development.
authors: Department of Safety Assessment, 709 Swedeland Road, King of Prussia, PA 19406, USA. Deidre.A.Dalmas@gsk.com
authors: Deidre A
authors: DA
authors: Dalmas
authors: Marshall S
authors: MS
authors: Scicchitano
authors: David
authors: D
authors: Mullins
authors: Angela
authors: A
authors: Hughes-Earle
authors: Kay
authors: K
authors: Tatsuoka
authors: Michal
authors: M
authors: Magid-Slav
authors: Kendall S
authors: KS
authors: Frazier
authors: Heath C
authors: HC
authors: Thomas
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D018818:Fenoldopam / Q000633:toxicity; D005819:Genetic Markers / Q000187:drug effects / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D057772:Vascular System Injuries / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology
chemical_list: D005819:Genetic Markers; D018818:Fenoldopam