Toxicogenomics – A Drug Development Perspective - Genomic Biomarkers for Pharmaceutical Development - page 126

TABLE 6.1 A Toxicogenomics Technology landscape

Molecular
Levels

Scientific Disciplines and their Representative
Molecular Technologies Data Type Readout

RNA Microarrays; next generation sequencing Transcriptomics Whole genome gene

expression data

Protein Resolution of complex mixtures for instance by 2D

gel electrophoreses coupled with MS and MS / MS
technologies and different ionization protocols

Proteomics Proteome information

Metabolite NMR and MS Metabolomics Metabolome information

constructing mechanistic and predictive toxicity. Furthermore, metabolomics uses endog-
enous metabolite signatures to determine the molecular mechanisms of drug actions and pre-
dict toxicity. Rapid advancement in mass spectrometry (MS) and nuclear magnetic resonance
(NMR) has driven the development of proteomics and metabolomics, which complement
transcriptomics [34-36] . However, in contrast to microarrays for transcriptomics, technolo-
gies for proteomics and metabolomics are limited by the huge range of analyte concentra-
tions involved (at least six orders of magnitude), because most existing instrumentations are
only capable of detecting more abundant species over those that are less abundant. This fun-
damental problem limits essentially all proteomic and metabolomic analyses to subsets of the
complete collections of proteins and metabolites, respectively. Despite this limitation, prot-
eomic and metabolomic approaches have fundamentally advanced the understanding of the
mechanisms of toxicity and adaptation to stress and injury.
Two key advantages accrue when applying toxicogenomics. First, the large quantity and
comprehensiveness of information that a single experiment can generate is much greater
than that which traditional experiments generate. Second, the advancement of computing
power and techniques enables these large amounts of information to be synthesized from dif-
ferent sources and experiments, and to be analyzed in novel ways. The sections below pro-
vide an overview of technologies used in toxicogenomics.

6.3.1 Transcriptomics
The transcriptome is the molecular compartment of transiently expressed genes.
Transcriptomic technology is a means to detect the transcription of genetic information
encoded within DNA into RNA (e.g., mRNA) molecules that are then translated into the
proteins that perform most of the critical biological functions of cells [37] . Understanding
the transcriptome is essential for interpreting the functional elements of the genome and
revealing the molecular constituents of cells and tissues, and also for understanding devel-
opment and disease. Transcriptomics can address all or a segment of the transcriptome,
from normal or diseased single cells to tissues. Depending on the techniques employed, it
can be used, for example, to catalog and annotate a cell's RNA complement, including cod-
ing as well as non-coding transcripts; to query the structure of the genes that give rise to
them, including exon / intron boundaries, transcription start sites, splicing patterns and even
gene fusion events; and to aid in mapping interactive networks. Perhaps most importantly,