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.