Microarray analysis of the temporal response of skeletal muscle to methylprednisolone: comparative analysis of two dosing regimens.
The transcriptional response of skeletal muscle to chronic corticosteroid exposure was examined over 168 h and compared with the response profiles observed following a single dose of corticosteroid. Male adrenalectomized Wistar rats were given a constant-rate infusion of 0.3 mg x kg(-1) x h(-1) methylprednisolone for up to 7 days via subcutaneously implanted minipumps. Four control and forty drug-treated animals were killed at ten different time points during infusion. Liver total RNAs were hybridized to 44 individual Affymetrix REA230A gene chips. Previously, we described a filtration approach for identifying genes of interest in microarray data sets developed from tissues of rats treated with methylprednisolone (MPL) following acute dosing. Here, a similar approach involving a series of three filters was applied sequentially to identify genes of interest. These filters were designed to eliminate probe sets that were not expressed in the tissue, not regulated by the drug, or did not meet defined quality control standards. Filtering eliminated 86% of probe sets, leaving a remainder of 2,316 for further consideration. In a previous study, 653 probe sets were identified as MPL regulated following administration of a single (acute) dose of the drug. Comparison of the two data sets yielded 196 genes identified as regulated by MPL in both dosing regimens. Because of receptor downregulation, it was predicted that genes regulated by receptor-glucocorticoid response element interactions would exhibit tolerance in chronic profiles. However, many genes did not exhibit steroid tolerance, indicating that present perspectives on the mechanism of glucocorticoid action cannot entirely explain all temporal profiles.
Almon
Richard R
RR
Department of Pharmaceutical Sciences State University of New York at Buffalo, Buffalo, New York 14260, USA. almon@eng.buffalo.edu
DuBois
Debra C
DC
Yao
Zhenling
Z
Hoffman
Eric P
EP
Ghimbovschi
Svetlana
S
Jusko
William J
WJ
D000818:Animals; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*; D046228:Microarray Analysis; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D008775:Methylprednisolone