Underlying Mechanisms of Pharmacology and Toxicity of a Novel PPAR Agonist Revealed Using Rodent and Canine Hepatocytes
Yin Guo, Robert A. Jolly, Bartley W. Halstead, Thomas K. Baker, John P. Stutz, Melanie Huffman, John N. Calley, Adam West, Hong Gao, George H. Searfoss, Shuyu Li, Armando R. Irizarry, Hui-rong Qian, James L. Stevens and Timothy P. Ryan. Toxicological Sciences 96(2), 294–309 (2007).
A research team led by Timothy Ryan in the
Department of Investigative Toxicology at
Eli Lilly set out to understand the mechanisms
underlying species differences in the pharmacological
and toxicological responses to a novel PPAR
agonist, LY465608, observed in vivo. IPA analysis
of global gene expression changes induced
by LY465608 in dog and rat hepatocytes identified
species-specific abnormalities in toxicity-related
pathways and cellular processes. The novel
insights generated by IPA helped the team
propose a mechanism of species-specific toxic
effects, which may have a significant impact
on the development of compounds to treat metabolic
disorders.
Primary dog and rat hepatocytes treated with
the novel PPAR agonist LY465608 were used
as an in vitro model to explore mechanisms
of toxicity. IPA Functional Analysis of global
drug-induced gene expression changes was used
to understand which biological functions were
most significantly and differentially affected
by compound treatment in rat and dog hepatocytes.
In rat hepatocytes, IPA identified Lipid Metabolism
as the most significantly perturbed process,
a finding that was consistent with the known
pharmacology of LY465608. In contrast, IPA
identified Cell Death as the most significantly
perturbed biological process in dog hepatocytes,
a finding that was consistent with the liver
toxicity observed in LY465608-treated dogs.
Importantly, the team found that expression
changes in individual genes were subtle, but
when viewed collectively in the context of
pathways and functions, these data pointed
to specific mechanisms of toxicity.
IPA analysis of expression-based studies,
in combination with biochemical studies, provided
the Lilly team with a better understanding
of the differential pharmacology and toxicity
observed in rats and dogs in response to a
novel PPAR agonist, and represents a valuable
approach to future development of compounds
to treat metabolic disorders. |
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