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

• Published in: Chemical research in toxicology 2014-03, Vol.27 (3), p.421-432
• Main Authors: Hur, Junguk, Liu, Zhichao, Tong, Weida, Laaksonen, Reijo, Bai, Jane P. F
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Carnitine O-Palmitoyltransferase - genetics; Carnitine O-Palmitoyltransferase - metabolism; Databases, Factual; Down-Regulation - drug effects; Energy Metabolism - drug effects; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; gamma-Synuclein - genetics; gamma-Synuclein - metabolism; Gene Expression Profiling; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry; Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - toxicity; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Oxidative Phosphorylation - drug effects; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - metabolism; Proteolysis - drug effects; Rhabdomyolysis - chemically induced; Rhabdomyolysis - metabolism; Rhabdomyolysis - pathology
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx400409c

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.