Drug-Induced Rhabdomyolysis: From Systems Pharmacology Analysis to Biochemical Flux

The
goal of this study was to integrate systems pharmacology and
biochemical flux to delineate drug-induced rhabdomyolysis by leveraging
prior knowledge and publicly accessible data. A list of 211 rhabdomyolysis-inducing
drugs (RIDs) was compiled and curated from multiple sources. Extended
pharmacological network analysis revealed that the intermediators
directly interacting with the pharmacological targets of RIDs were
significantly enriched with functions such as regulation of cell cycle,
apoptosis, and ubiquitin-mediated proteolysis. A total of 78 intermediators
were shown to be significantly connected to at least five RIDs, including
estrogen receptor 1 (ESR1), synuclein gamma (SNCG), and janus kinase
2 (JAK2). Transcriptomic analysis of RIDs profiled in Connectivity
Map on the global scale revealed that multiple pathways are perturbed
by RIDs, including ErbB signaling and lipid metabolism pathways, and
that carnitine palmitoyl transferase 2 (CPT2) was in the top 1 percent
of the most differentially perturbed genes. CPT2
was downregulated by nine drugs that perturbed the genes significantly
enriched in oxidative phosphorylation and energy-metabolism pathways.
With statins as the use case, biochemical pathway analysis on the
local scale implicated a role for CPT2 in statin-induced perturbation
of energy homeostasis, which is in agreement with reports of statin–CPT2 interaction. Considering the complexity of human biology,
an integrative multiple-approach analysis composed of a biochemical
flux network, pharmacological on- and off-target networks, and transcriptomic
signature is important for understanding drug safety and for providing
insight into clinical gene–drug interactions.