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CELLULAR AND MOLECULAR

Circadian Variations in Rat Liver Gene Expression: Relationships to Drug Actions

Departments of Biological Sciences (R.R.A., W.L., D.C.D.) and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York (R.R.A., D.C.D., W.J.J.); New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York (R.R.A., W.J.J.); and Biomedical Engineering Department, Rutgers University, Piscataway, New Jersey (E.Y., I.P.A.)

Chronopharmacology is an important but under-explored aspect of therapeutics. Rhythmic variations in biological processes can influence drug action, including pharmacodynamic responses, due to circadian variations in the availability or functioning of drug targets. We hypothesized that global gene expression analysis can be useful in the identification of circadian-regulated genes involved in drug action. Circadian variations in gene expression in rat liver were explored using Affymetrix gene arrays. A rich time series involving animals analyzed at 18 time points within the 24-h cycle was generated. Of the more than 15,000 probe sets on these arrays, 265 exhibited oscillations with a 24-h frequency. Cluster analysis yielded five distinct circadian clusters, with approximately two thirds of the transcripts reaching maximal expression during the dark/active period of the animal. Of the 265 probe sets, 107 were identified as having potential therapeutic importance. The expression levels of clock genes were also investigated in this study. Five clock genes exhibited circadian variation in the liver, and data suggest that these genes may also be regulated by corticosteroids.

Address correspondence to: Dr. Richard R. Almon, Department of Biological Sciences, 107 Hochstetter Hall, State University of New York at Buffalo, Buffalo, NY 14260. E-mail: almon{at}eng.buffalo.edu