Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis

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.