PMID- 24422454 OWN - NLM STAT- MEDLINE DCOM- 20141117 LR - 20140318 IS - 1520-5010 (Electronic) IS - 0893-228X (Linking) VI - 27 IP - 3 DP - 2014 Mar 17 TI - Drug-induced rhabdomyolysis: from systems pharmacology analysis to biochemical flux. PG - 421-32 LID - 10.1021/tx400409c [doi] AB - 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. FAU - Hur, Junguk AU - Hur J AD - Department of Neurology, University of Michigan , Ann Arbor, Michigan 48109, United States. FAU - Liu, Zhichao AU - Liu Z FAU - Tong, Weida AU - Tong W FAU - Laaksonen, Reijo AU - Laaksonen R FAU - Bai, Jane P F AU - Bai JP LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140128 PL - United States TA - Chem Res Toxicol JT - Chemical research in toxicology JID - 8807448 RN - 0 (Estrogen Receptor alpha) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Pharmaceutical Preparations) RN - 0 (gamma-Synuclein) RN - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase) RN - EC 2.7.10.2 (Janus Kinase 2) SB - IM MH - Apoptosis/drug effects MH - Carnitine O-Palmitoyltransferase/genetics/metabolism MH - Databases, Factual MH - Down-Regulation/drug effects MH - Energy Metabolism/drug effects MH - Estrogen Receptor alpha/genetics/metabolism MH - Gene Expression Profiling MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry/metabolism/toxicity MH - Janus Kinase 2/genetics/metabolism MH - Muscle, Skeletal/drug effects/metabolism MH - Oxidative Phosphorylation/drug effects MH - Pharmaceutical Preparations/chemistry/*metabolism MH - Proteolysis/drug effects MH - Rhabdomyolysis/chemically induced/*metabolism/pathology MH - gamma-Synuclein/genetics/metabolism EDAT- 2014/01/16 06:00 MHDA- 2014/11/18 06:00 CRDT- 2014/01/16 06:00 PHST- 2014/01/16 06:00 [entrez] PHST- 2014/01/16 06:00 [pubmed] PHST- 2014/11/18 06:00 [medline] AID - 10.1021/tx400409c [doi] PST - ppublish SO - Chem Res Toxicol. 2014 Mar 17;27(3):421-32. doi: 10.1021/tx400409c. Epub 2014 Jan 28.