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data to improve pre-clinical drug safety and toxicity assessment in order to reduce the late
stage attrition rate in drug discovery and development. DrugMatrix was initially constructed
using the CodeLink RU1 rat microarray platform (GE Healthcare, Chalfont St Giles, UK), and
then extended to study transcriptional effects on the whole genome RG230_2.0 rat GeneChip
array platform (Affymetrix, CA, USA). The most recent release of DrugMatrix, now owned
ntp.niehs.nih.gov
/
drugmatrix
/
index.html
, accessed on Nov. 22, 2012), contains data on some
636 compounds. Gene expression profiling was conducted for seven different tissue types
(liver, kidney, heart, bone marrow, thigh muscle, spleen, and intestine), and for rat primary
hepatocytes, for a total of more than 4100 drug-dose-time-tissue combinations. The extensive
database allows for improved mechanistic understanding and interpretation of drug signa-
ture through the availability of more curated genes within the whole genome. The analysis of
array data showed that the compounds with low margins in a four-day rat toxicology study
were predicted to have phospholipase D (PLD) and hepatotoxicity
[220]
. PLD is an enzyme
that catalyzes the hydrolysis of phosphatidyl choline (PC) to generate phosphatidic acid and
choline. GPI-PLD [glycosylphosphatidylinositol (GPI)-specific phospholipase D (PLD)] is a
secreted mammalian enzyme that specifically cleaves GPI-anchored proteins. In addition,
the enzyme has been shown to cleave GPI anchor intermediates in cell lysates
[221,222]
. The
expression of PLD may be associated with PPARα-induced hepatotoxicity through a complex
interaction with nuclear receptors including CAR and PXR
[222,223]
. DrugMatrix has been
applied to assist scientists in the selection of the leads and drug candidates at the earliest and
most-cost-effective stages of drug discovery. Recent publications have demonstrated that cou-
pling gene expression profiling with traditional toxicity measurements provides a powerful
tool for understanding individual compound effects in rat.
The Japanese Toxicogenomics Project is a five-year collaborative project (2002-2007) ini-
tiated by a consortium consisting of the Japanese government and 15 pharmaceutical com-
panies. The project produced the 'Toxicogenomics Project-Genomics Assisted Toxicity
Evaluation system' (TG-GATEs), a large-scale database of transcriptomics and pathology
data potentially useful for predicting the toxicity of new chemical entities
[224]
. Conventional
in vivo
toxicology data were collected from both single and repeat dosing studies on rats,
and the gene expression was measured for the liver (and kidney in some cases). To provide
information on species differences, gene expression was also measured
in vitro
in rat and
in human hepatocytes treated with the chemicals. Approximately 130 chemicals, primarily
medicinal compounds, were tested at multiple doses. Gene expression was analyzed using
Affymetrix GeneChip arrays (Hgu133plus2 and rat233a). For each compound, the gene
expression data were collected within four separate experiments:
in vitro
human hepato-
cytes exposures,
in vitro
rat primary hepatocytes exposures, liver and kidney from
in vivo
sin-
gle dose rat exposures, and liver and kidney from
in vivo
repeat dose rat exposures. Within
in vitro
exposures, duplicate samples were collected at four doses (control, low, medium,
high) across three time points (2, 8, and 24 hour exposure). Within the single dose
in vivo
exposures, triplicate samples were collected at the four doses across four time points (3, 6,
9, and 24 hours). Within the repeat dose
in vivo
exposures, samples were collected at 4, 8,
15, and 29 days following daily dosing with the same four doses. These data were initially
made available through the TG-GATE website (
http:
//
toxico.nibio.go.jp
/
open-tggates
/
search.
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