| RRC ID |
74468
|
| Author |
Shirayanagi T, Kazaoka A, Watanabe K, Qu L, Sakamoto N, Hoshino T, Ito K, Aoki S.
|
| Title |
Weak complex formation of adverse drug reaction-associated HLAB57, B58, and B15 molecules.
|
| Journal |
Toxicol In Vitro
|
| Abstract |
The combination of certain human leukocyte antigen (HLA) polymorphisms with administration of certain drugs shows a strong correlation with developing drug hypersensitivity. Examples of typical combinations are HLA-B*57:01 with abacavir and HLA-B*15:02 with carbamazepine. However, despite belonging to the same serotype, HLA-B*57:03 and HLA-B*15:01 are not associated with drug hypersensitivity. Recent studies have shown that several HLA polymorphisms are associated with multiple drugs rather than a single drug, all resulting in drug hypersensitivity. In this study, we compared the molecular structures and intracellular localization of HLA-B*57:01, HLA-B*58:01, and HLA-B*15:02, which pose risks for developing drug hypersensitivity, as well as HLA-B*57:03 and HLA-B*15:01 that do not present such risks. We found that HLA molecules posing risks have a low affinity for the subunit β2-microglobulin; notably, the weak hydrogen bond formed via Gln96 of the HLA molecule contributes to this behavior. We also clarified that these HLA molecules are easily accumulated in the endoplasmic reticulum, exhibiting a low expression on the cell surface. Considering that these hypersensitivity risk-associated HLA molecules form complexes with β2-microglobulin and peptides in the endoplasmic reticulum, we assumed that their low complex formation ability in the endoplasmic reticulum facilitates the interaction with multiple drugs.
|
| Volume |
82
|
| Pages |
105383
|
| Published |
2022-8-1
|
| DOI |
10.1016/j.tiv.2022.105383
|
| PII |
S0887-2333(22)00080-7
|
| PMID |
35568130
|
| MeSH |
Carbamazepine / toxicity
Drug Hypersensitivity* / genetics
Drug-Related Side Effects and Adverse Reactions*
HLA Antigens / genetics
HLA-B Antigens / chemistry
HLA-B Antigens / metabolism
Humans
|
| IF |
2.959
|
| Resource |
| Human and Animal Cells |
HeLa |
