Pharmacodynamics and pharmacogenomics of diverse receptor-mediated effects of methylprednisolone in rats using microarray analysis

Corticosteroids such as methylprednisolone (MPL) produce many of their anti-inflammatory, immunosuppressive, and exaggerated physiological effects by receptor and gene-mediated mechanisms. The temporal pattern of change in four genes in rat tissues was measured by quantitative Northern hybridization and rtPCR after a single dose of MPL. Two profiles were observed: two genes with enhanced expression showed a slow onset and moderate rate of decline within a 24 hr time frame while two genes with reduced expression exhibited a rapid onset and prolonged suppression over a greater than or equal to 72 hr time span. These patterns are consistent with and rationalized by pharmacodynamic expectations based on earlier models. cDNA microarrays used to assess the expression levels of 5200 genes at one optimal time-point showed marked variation in baseline values. Of these, 20 genes showed statistically significant enhanced expression with increases ranging from 130 to 1690%, 31 genes exhibited reduced expression ranging from 31 to 72% of control. Many genes could be categorized as affecting acute phase/immune response, energy metabolism, microsomal metabolism, and hepatic function. These studies provide the first simultaneous assessment of the diversity in pharmacogenomic effects of corticosteroids. They also provide some insight into the advantages and limitations of microarray measurements in regard to the pharmacodynamics of drugs having complex, multi-faceted, and integrated mechanisms of action.