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The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury

奈韦拉平 肝损伤 皮质酮 药品 药理学 医学 化学 内科学 免疫学 人类免疫缺陷病毒(HIV) 激素 病毒载量 抗逆转录病毒疗法
作者
Alison Jee,Samantha Christine Sernoskie,Jack Uetrecht
出处
期刊:Toxicological Sciences [Oxford University Press]
卷期号:200 (1): 146-164
标识
DOI:10.1093/toxsci/kfae054
摘要

Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI.
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