Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Clin Transl Sci. 2023 Jan;16(1):37-42. doi: 10.1111/cts.13424. Epub 2022 Oct 4.
Idiosyncratic drug-induced liver injury (DILI) remains an important clinical problem, both during drug development and the prescription of a range of licensed drugs. Although rare, the consequences are serious. Ongoing studies on genetic risk factors for DILI, especially genomewide association studies, have resulted in the identification of a number of genetic risk factors, including particular HLA alleles and a few non-HLA genes, both immune-related and metabolic. Some non-HLA associations, such as N-acetyltransferase 2 in isoniazid DILI and interferon regulatory factor 6 in interferon-beta DILI are likely to be drug-specific due to the role of the associated gene, but there is also evidence for polygenic susceptibility involving pathways such as oxidative and endoplasmic reticulum stress and mitochondrial function for DILI induced by multiple drugs. Increased knowledge of genetic risk factors should assist in better understanding underlying DILI mechanisms and help improve methods for identifying hepatotoxic drugs early in development. HLA allele-specific T cell proliferation together with in silico prediction of drug binding to specific HLA proteins have confirmed genetic findings for certain common causes of DILI. However, studies in hepatocytes exposed to high drug concentrations suggest toxicity that is not dependent on genotype also occurs. It seems likely that susceptibility to DILI involves several genetic risk factors combining with other factors that affect drug levels. Despite recent progress in detecting genetic risk factors for DILI, low positive predictive values mean that general implementation of genotyping prior to prescription of potentially hepatotoxic drugs is not useful currently.
特发性药物性肝损伤（DILI）仍然是一个重要的临床问题，无论是在药物开发期间还是在开具一系列许可药物时。尽管罕见，但后果严重。正在进行的 DILI 遗传风险因素研究，特别是全基因组关联研究，已经确定了一些遗传风险因素，包括特定的 HLA 等位基因和一些非 HLA 基因，包括免疫相关和代谢相关的基因。一些非 HLA 相关性，如异烟肼 DILI 中的 N-乙酰转移酶 2 和干扰素-β DILI 中的干扰素调节因子 6，由于相关基因的作用，可能是药物特异性的，但也有证据表明涉及氧化和内质网应激和线粒体功能等途径的多基因易感性，用于多种药物引起的 DILI。对遗传风险因素的更多了解应有助于更好地了解潜在的 DILI 机制，并有助于改进在开发早期识别肝毒性药物的方法。HLA 等位基因特异性 T 细胞增殖以及药物与特定 HLA 蛋白结合的计算机预测，证实了某些常见 DILI 病因的遗传发现。然而，在暴露于高药物浓度的肝细胞中的研究表明，也存在不依赖于基因型的毒性。似乎 DILI 的易感性涉及几个遗传风险因素与其他影响药物水平的因素相结合。尽管在检测 DILI 的遗传风险因素方面取得了最近的进展，但低阳性预测值意味着目前在开具潜在肝毒性药物之前进行基因分型的广泛实施并不有用。
