title: Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.
abstract: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious cutaneous adverse reactions. We mined the approved labels in Drugs@FDA, identified the SJS/TEN list of 259 small molecular drugs and biologics, and conducted systems pharmacological network analyses. Pharmacological network analysis revealed that drugs with treatment-related SJS and/or TEN are pharmacologically diverse and that the largest subnetwork is associated with antiepileptic drugs and their pharmacological targets. Our pharmacological network analysis identified CTNNB1 [catenin (cadherin-associated protein), beta 1, 88 kDa] as a significant intermediator. This protein is involved in maintaining the functional integrity of the epithelium through regulating cell growth and adhesion between cells in various organs, including the skin. Leveraging a publicly accessible genome-wide transcriptional expression database, we found that human leukocyte antigen-related (HLA) genes were significantly perturbed by various SJS/TEN-inducing drugs. Notably, carbamazepine (CBZ) perturbed several HLA genes, among which HLA-DQB1*0201 was reportedly shown to be associated with CBZ-induced SJS/TEN in caucasians. In short, systems analysis by leveraging a publicly accessible knowledge base and databases could produce meaningful results for further mechanistic investigation. Our study sheds light on the utility of systems pharmacology analysis for gaining insight into clinical drug toxicity.
authors: ‡Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Junguk
authors: J
authors: Hur
authors: §Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, United States.
authors: ChunSheng
authors: C
authors: Zhao
authors: §Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, United States.
authors: Jane P F
authors: JP
authors: Bai
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects*; D002220:Carbamazepine / Q000009:adverse effects; D062313:Databases, Pharmaceutical; D005786:Gene Expression Regulation / Q000187:drug effects; D059866:HLA-DQ beta-Chains / Q000235:genetics; D006801:Humans; D012307:Risk Factors; D054852:Small Molecule Libraries / Q000009:adverse effects*; D013262:Stevens-Johnson Syndrome / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; C495270:CTNNB1 protein, human; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D054852:Small Molecule Libraries; D051176:beta Catenin; D002220:Carbamazepine