Toxicogenomics and cross-species biomarker discovery: applications in drug discovery and safety assessment.
Toxicogenomics has evolved into a useful technique for providing greater mechanistic insights into adverse effects that will spur the development of novel approaches for identifying and understanding toxicity issues. The ability to capture a snapshot of the transcriptome at any given time during the development of an adverse phenotype allows unprecedented molecular views into the dynamic physiological changes that are occurring on either time or dose continuum for a toxicology study of interest advancing our basic knowledge of adverse events, and providing the necessary scientific framework for developing new strategies and tools for safety assessment programs. The development of an effective subset of cost effective devices for identifying toxicity earlier in the drug development process will help identify the most promising candidate compounds to move forward leading to a reduction in compound attrition due to toxicity. In addition, there is a need in the pharmaceutical industry to develop safety and efficacy biomarkers that are relevant to multiple species such as rat, dog, and human. Genomics provides an opportunity to discover novel cross-species biomarkers for identifying phenotypes such as liver fibrosis, especially if the biomarkers are tissue specific secreted proteins that can be monitored in the serum. This review includes an example of how databases from multiple species, in this case rat and human tissues, can be utilized to identify candidate cross-species diagnostic markers of hepatitis and fibrosis. This study illustrates a genomic approach for identifying candidate cross-species biomarkers of cirrhosis/fibrosis for humans and rats, and a previously known biomarker of fibrosis (APOA1) and a novel candidate biomarker of fibrosis, FETUB were identified. As more "omic" databases are built, a reservoir of molecular information will become available for toxicologist to gain more extensive views on the physiological alterations induced by adverse events, which will inevitably lead to the development of better tools for predicting, identifying, categorizing, and determining cross-species impact of the toxicity and ultimate provide a novel scientific scaffold for improving safety assessment protocols.
Orr
Michael S
MS
Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Office of Clinical Pharmacology, Silver Spring, MD, 20903-0002, USA.