Elucidating the Mechanisms Underlying Interindividual Differences in the Onset of Adverse Drug Reactions

Idiosyncratic drug toxicities (IDTs) pose a significant challenge; they are marked by life-threatening adverse reactions that emerge aftermarket release and are influenced by intricate genetic and environmental variations. Recent genome-wide association studies have highlighted a strong correlation...

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 2024/06/01, Vol.47(6), pp.1079-1086
Main Author: Aoki, Shigeki
Format: Article
Language:English
Subjects:
Animal models
Animals
drug-induced liver injury
Drug-Related Side Effects and Adverse Reactions
Genetic diversity
Genome-wide association studies
Histocompatibility antigen HLA
HLA Antigens - genetics
HLA Antigens - immunology
human leukocyte antigen
Humans
idiosyncratic drug toxicity
Immune response
immune tolerance
Immunological tolerance
Mice
Mice, Transgenic
Molecular modelling
Polymorphism, Genetic
Reviews
Side effects
skin rash
Transgenic mice
transgenic mouse model
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Summary:Idiosyncratic drug toxicities (IDTs) pose a significant challenge; they are marked by life-threatening adverse reactions that emerge aftermarket release and are influenced by intricate genetic and environmental variations. Recent genome-wide association studies have highlighted a strong correlation between specific human leukocyte antigen (HLA) polymorphisms and IDT onset. This review provides an overview of current research on HLA-mediated drug toxicities. In the last six years, HLA-transgenic (Tg) mice have been instrumental in advancing our understanding of these underlying mechanisms, uncovering systemic immune reactions that replicate human drug-induced immune stimulation. Additionally, the potential role of immune tolerance in shaping individual differences in adverse effects highlights its relevance to the interplay between HLA polymorphisms and IDTs. Although HLA-Tg mice offer valuable insights into systemic immune reactions, further exploration is essential to decipher the intricate interactions that lead to organ-specific adverse effects, especially in organs such as the skin or liver. Navigating the intricate interplay of HLA, which may potentially trigger intracellular immune responses, this review emphasizes the need for a holistic approach that integrates findings from both animal models and molecular/cellular investigations. The overarching goal is to enhance our comprehensive understanding of HLA-mediated IDTs and identify factors shaping individual variations in drug reactions. This review aims to facilitate the development of strategies to prevent severe adverse effects, address existing knowledge gaps, and provide guidance for future research initiatives in the field of HLA-mediated IDTs.
ISSN:0918-6158
1347-5215
1347-5215
DOI:10.1248/bpb.b24-00072