Mechanistic toxicogenomic analysis of WAY-144122 administration in Sprague-Dawley rats.

ABSTRACT

Application of global gene expression analysis in the study of mechanisms of toxicity could provide a more comprehensive interpretation of the molecular basis of drug action. WAY-144122 has pharmacological activity against several targets improving insulin responsiveness and favorably altering lipid profiles. Normal rats treated with suprapharmacological doses of WAY-144122 for 28 days exhibited drug-related effects in the liver and ovary. To determine the molecular mechanism underlying these effects, we employed global gene expression profiling to measure RNA levels in these target organs obtained from WAY-144122-treated rats administered test article for 1, 3, 7, and 14 days. Genes altered in expression by WAY-144122 were functionally categorized and related to their biological activity. In the liver, WAY-144122 caused a widespread up-regulation of genes involved in lipid mobilization, peroxisomal proliferation, and fatty acid beta-oxidation. In the ovary, we observed reduced expression of genes encoding luteinizing hormone receptor, follistatin, and enzymes in the estradiol synthesis pathway. Transcriptional changes in both organs precede histopathological effects. Profiling analysis allowed us to formulate hypotheses for molecular mechanisms underlying the physiological observations. In the liver, transcriptional changes suggest that WAY-144122 induced increased metabolic activity and peroxisomal proliferation resulting in increased liver weight and hepatocellular hypertrophy. We propose decreased estradiol synthesis as the underlying mechanism for the observed follicular atrophy in the ovary. Importantly, in this study, we have identified potential molecular mechanisms of drug effect in expression profiles before observation of physiological changes.