title: The Possible Mechanism of Idiosyncratic Lapatinib-Induced Liver Injury in Patients Carrying Human Leukocyte Antigen-DRB1*07:01.
abstract: Idiosyncratic lapatinib-induced liver injury has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01. In order to investigate its mechanism, interaction of lapatinib with HLA-DRB1*07:01 and its ligand peptide derived from tetanus toxoid, has been evaluated in vitro. Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01. Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove. These results indicate that lapatinib affects the ligand binding to HLA-DRB1*07:01 and idiosyncratic lapatinib-induced liver injury might be triggered by this mechanism. This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirasawa
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Hagihara
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Okudaira
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000503:physiopathology*; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D000077341:Lapatinib; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011799:Quinazolines / Q000009:adverse effects*; D013745:Tetanus Toxoid / Q000378:metabolism
chemical_list: D059811:HLA-DRB1 Chains; C527714:HLA-DRB1*07:01:01 antigen; D011799:Quinazolines; D013745:Tetanus Toxoid; D000077341:Lapatinib