Biology Reference
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offers an opportunity for improving the understanding of biological pathways that are modu-
lated by a drug. Such a need is apparent when it comes to achieving a better assessment of
safety issues throughout the entire drug development cycle
[178-180]
. Gene expression profil-
ing identifies critical, toxicologically-relevant genes and signal-response pathways, and prom-
ises to improve risk assessment and safety evaluation practices. By examining alterations in
gene expression in response to drugs, it is possible to generate hypotheses about the under-
lying mechanisms of toxicity, which could be crucial for the identification of potential safety
liabilities early in the drug development process
[181-183]
. Public annotations of functional
and biological aspects of the rat and human genome such as cellular, molecular, and biologi-
cal components have increased the level of understanding of complicated co-regulation within
and among pathways and genes
[184,185]
. When transcriptional data was linked to pheno-
type, toxicogenomics became very useful in predicting drug-induced toxicity and understand-
ing the underlying mechanisms.
A great deal of mechanistic toxicogenomics research has focused on hepatotoxicity
because a wealth of published and proprietary gene expression information is available
for the liver. Clearly, the lessons learned from the study of hepatotoxicity may be extensi-
ble to other tissue and organ toxicities, such as those for the kidney, heart, and bone mar-
row
[186-189]
. About a decade ago, by using microarrays in rat hepatocytes, Waring et al.
reported that the mechanism of action for prototypical toxicants could be discerned
[190]
.
With the assumption that drug toxicity is accompanied by transcriptional changes in gene
expression that are causally linked to downstream of the toxicity
[191]
, Waring and his col-
leagues conducted a large-scale gene expression analysis in order to gain an enhanced under-
standing of the pathogenesis of drug-induced phosphilipidosis using the human hepatoma
HepG2 cell line. This study established four affected pathways which contribute to the for-
mation of phosphilipidosis
[192]
. Altered gene expression was consistent with lysosomal
phospholipase inhibition with increased expression of phospholipid degradation genes such
as N-acylsphingosine amidohydrolase 1 and sphingomyelin phosphodiesterase. There was
also a role for reduced lysosomal enzyme transport demonstrated by decreased expression of
genes such as adaptor-related protein complex 1 sigma 1 that transports lysosomal enzymes
between the Golgi network and the lysosyme. The results also indicated a role for increased
phospholipid and cholesterol biosynthesis (stearoyl-CoA desaturase and HMGCoA synthe-
sis, respectively), both of which are triggers for phosphilipidosis
[193]
. Thus, phosphilipido-
sis results from the combination of events involving both increased synthesis and decreased
degradation of phospholipids. In addition, the extension of this study identified a set of 12
marker genes for predicting phosphilipidosis
[194]
.
In another example, Burczynski et al. used HepG2 to profile cellular gene expression after
human exposure to mechanistically unrelated drugs (cytotoxic anti-inflammatory drugs and
DNA-damaging agents) with a low-density DNA microarray containing a set of 250 human
genes
[195]
. The study was able to identify a reproducible, small, common set of genes from
two classes of drugs. This gene set was used to distinguish compounds from these two
classes based on a cluster analysis
[195]
. Discriminatory analysis identified genes involved in
DNA repair, xenobiotic metabolism, cell-cycle control, apoptosis and transcriptional activa-
tion. Together with others, these early transcription-profiling studies demonstrated that drug
treatment can trigger expressional alterations in many genes which may be linked to putative
modes of action associated with adverse events
[196]
.
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