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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
2秒前
3秒前
GL发布了新的文献求助10
3秒前
乐乐应助如意枫叶采纳,获得10
3秒前
4秒前
史念薇发布了新的文献求助10
4秒前
xixi完成签到 ,获得积分10
4秒前
6秒前
青野发布了新的文献求助10
8秒前
11秒前
12秒前
高贵梦露完成签到,获得积分10
12秒前
14秒前
16秒前
量子星尘发布了新的文献求助10
17秒前
如意枫叶发布了新的文献求助10
18秒前
18秒前
19秒前
19秒前
21秒前
22秒前
23秒前
赘婿应助GL采纳,获得10
23秒前
24秒前
24秒前
Archer宇完成签到,获得积分10
24秒前
狸花小喵发布了新的文献求助10
26秒前
科研废物完成签到 ,获得积分10
26秒前
27秒前
28秒前
29秒前
30秒前
32秒前
33秒前
潇湘雪月发布了新的文献求助10
34秒前
34秒前
35秒前
ding应助咩咩羊采纳,获得10
35秒前
36秒前
quququ发布了新的文献求助30
37秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989263
求助须知:如何正确求助?哪些是违规求助? 3531418
关于积分的说明 11253814
捐赠科研通 3270066
什么是DOI,文献DOI怎么找? 1804884
邀请新用户注册赠送积分活动 882084
科研通“疑难数据库(出版商)”最低求助积分说明 809136