Toxicogenomics – A Drug Development Perspective - Genomic Biomarkers for Pharmaceutical Development - page 125

been on the market and used by a large and diverse population [8-10] . The recent advent of
in silico (i.e., using computer software) methodologies and high-throughput in vitro (cell cul-
ture) screenings has alleviated some, but not all, of these challenges by providing a more effi-
cient and effective way to develop drugs. The emerging research field technology known as
toxicogenomics holds great potential for improving drug safety assessment, and consequently
the drug discovery and development process. This chapter is aimed at discussing the potential
applications and future challenges of toxicogenomics in drug discovery and development.
6.2 THE CONCEPT OF TOXICOGENOMICS
Toxicogenomics is a field of science that studies toxicology with genomics and other high-
throughput molecular technologies and bioinformatics [11] . Typically, it applies transcript, protein
and / or metabolite profiling technologies to investigate the interaction between genes / proteins /
metabolites and environmental stress in disease causation and toxicity. The concept of toxicog-
enomics was first introduced in 1999, inspired by the rapid advancement of microarray tech-
nologies [12] . The field has quickly expanded by including proteomics, metabolomics and other
new high-throughput technologies [13-15] . As a marriage of data-rich omics approaches with
bioinformatics, toxicogenomics requires expertise from diverse fields ranging from toxicology,
genetics, and molecular biology to computational science and bioinformatics [16-18] . The appli-
cation of toxicogenomics offers an opportunity to identify the biological pathways and processes
affected by exposure to pharmaceutical compounds and / or xenobiotics. It endeavors to elucidate
molecular mechanisms involved in toxicity and to derive molecular expression patterns (i.e.,
molecular biomarkers) that predict toxicity or the genetic susceptibility [19-21] . Examining the
patterns of altered molecular expressions caused by specific exposures can reveal how toxicants
act and create their effects [22-24] . In addition, identification of toxicity pathways and potential
modes of action allow for a more thorough understanding of safety issues. Increased understand-
ing of a compound's mode of action can be used to predict toxicity. This ability is expected to
reduce the attrition rate of new molecular entities and thus decrease the cost of developing new
drugs. Indeed, there are high expectations that toxicogenomics in drug development will better
predict / assess potential drug toxicity, and hence reduce attrition rates [25] . In the past 20 years,
toxicogenomics has improved current approaches and led to novel predictive approaches for
studying disease risk [26,27] . Most large pharmaceutical companies are now using the toxicog-
enomics approach as a predictive toxicology tool, with the goal of decreasing the drug-induced
adverse reactions and thus reducing the drug attrition rate [28-30] . Toxicogenomics has enjoyed
widespread attention as an alternative means of studying the underlying molecular mechanisms
of toxicity and of addressing challenges that are difficult to overcome using conventional toxicol-
ogy methods [31-33] .
6.3 TH E TECHNOLOGY LANDSCAPE OF TOXICOGEN OMICS
Toxicogenomics utilizes several technology platforms with an emphasis on profiling
transcripts (or genes), proteins, and metabolites ( Table 6.1 ). Specifically, a wide range of bio-
logical assay platforms, such as transcriptomics and proteomics, have been employed in