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The Possible Mechanism of Idiosyncratic Lapatinib-Induced Liver Injury in Patients Carrying Human Leukocyte Antigen-DRB1*07:01.

Hirasawa M, Hagihara K, Okudaira N, Izumi T - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Binding assay results.The binding of ligand peptides to HLA-DRB1*07:01 (a) and DRB1*15:01 (b) after 24 h of incubation in the absence and presence of three drugs, lapatinib, amoxicillin and lumiracoxib are shown. Plots show mean ± s.d. of triplicates. *P < 0.01; **P<0.05 (compared with counts in the absence of each drug).
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pone.0130928.g003: Binding assay results.The binding of ligand peptides to HLA-DRB1*07:01 (a) and DRB1*15:01 (b) after 24 h of incubation in the absence and presence of three drugs, lapatinib, amoxicillin and lumiracoxib are shown. Plots show mean ± s.d. of triplicates. *P < 0.01; **P<0.05 (compared with counts in the absence of each drug).

Mentions: To evaluate the effects of drugs on HLA-peptide interactions, DELFIA-based binding assay was conducted. The binding assay system was verified by competition of the unlabeled positive and negative control peptides against biotinylated ligand peptides. The positive control peptides successfully inhibited the binding of ligand peptides, but the negative control peptides did not (data not shown). Then, we evaluated the effects of three drugs, lapatinib, that is clinically related to DRB1*07:01 specific liver injury, and amoxicillin and lumiracoxib, that are not related to it, on the binding of its ligand peptide to each HLA-DR (DRB1*07:01 as the test allele and DRB1*15:01 as the control allele). Interestingly, lapatinib increased TT peptide binding to HLA-DRB1*07:01 in a dose-dependent manner, whereas amoxicillin and lumiracoxib did not exhibit increment of peptide binding for both alleles. These results indicate the observed effect is lapatinib specific (Fig 3). The enhancing effects of lapatinib were statistically significant (P <0.05) for DRB1*07:01 at 100 times lower concentrations than for DRB1*15:01, which indicates the allele preference of lapatinib for DRB1*07:01 over DRB1*15:01. Lapatinib did not exhibit any autofluorescence in this assay condition. Lapatinib did not show a tendency to affect the affinity of ligand peptide (data not shown), which is consistent with the previous report where addition of abacavir did not shift the IC50 of ligand peptides [12]. Amoxicillin and lumiracoxib decreased the binding of ligand peptide to HLA-DRB1*07:01 significantly, but their effects were not in dose-dependent manners.


The Possible Mechanism of Idiosyncratic Lapatinib-Induced Liver Injury in Patients Carrying Human Leukocyte Antigen-DRB1*07:01.

Hirasawa M, Hagihara K, Okudaira N, Izumi T - PLoS ONE (2015)

Binding assay results.The binding of ligand peptides to HLA-DRB1*07:01 (a) and DRB1*15:01 (b) after 24 h of incubation in the absence and presence of three drugs, lapatinib, amoxicillin and lumiracoxib are shown. Plots show mean ± s.d. of triplicates. *P < 0.01; **P<0.05 (compared with counts in the absence of each drug).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476721&req=5

pone.0130928.g003: Binding assay results.The binding of ligand peptides to HLA-DRB1*07:01 (a) and DRB1*15:01 (b) after 24 h of incubation in the absence and presence of three drugs, lapatinib, amoxicillin and lumiracoxib are shown. Plots show mean ± s.d. of triplicates. *P < 0.01; **P<0.05 (compared with counts in the absence of each drug).
Mentions: To evaluate the effects of drugs on HLA-peptide interactions, DELFIA-based binding assay was conducted. The binding assay system was verified by competition of the unlabeled positive and negative control peptides against biotinylated ligand peptides. The positive control peptides successfully inhibited the binding of ligand peptides, but the negative control peptides did not (data not shown). Then, we evaluated the effects of three drugs, lapatinib, that is clinically related to DRB1*07:01 specific liver injury, and amoxicillin and lumiracoxib, that are not related to it, on the binding of its ligand peptide to each HLA-DR (DRB1*07:01 as the test allele and DRB1*15:01 as the control allele). Interestingly, lapatinib increased TT peptide binding to HLA-DRB1*07:01 in a dose-dependent manner, whereas amoxicillin and lumiracoxib did not exhibit increment of peptide binding for both alleles. These results indicate the observed effect is lapatinib specific (Fig 3). The enhancing effects of lapatinib were statistically significant (P <0.05) for DRB1*07:01 at 100 times lower concentrations than for DRB1*15:01, which indicates the allele preference of lapatinib for DRB1*07:01 over DRB1*15:01. Lapatinib did not exhibit any autofluorescence in this assay condition. Lapatinib did not show a tendency to affect the affinity of ligand peptide (data not shown), which is consistent with the previous report where addition of abacavir did not shift the IC50 of ligand peptides [12]. Amoxicillin and lumiracoxib decreased the binding of ligand peptide to HLA-DRB1*07:01 significantly, but their effects were not in dose-dependent manners.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

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.

No MeSH data available.


Related in: MedlinePlus