National Institute of Environmental Health Sciences Microarray Group, National Institutes of Health (NIH), Research Triangle Park, NC 27709, USA.
Hepatology. 2010 Jan;51(1):227-36. doi: 10.1002/hep.23330.
The diagnosis and management of drug-induced liver injury (DILI) is hindered by the limited utility of traditional clinical chemistries. It has recently been shown that hepatotoxicants can produce compound-specific changes in the peripheral blood (PB) transcriptome in rodents, suggesting that the blood transcriptome might provide new biomarkers of DILI. To investigate in humans, we used DNA microarrays as well as serum metabolomic methods to characterize changes in the transcriptome and metabolome in serial PB samples obtained from six healthy adults treated with a 4-g bolus dose of acetaminophen (APAP) and from three receiving placebo. Treatment did not cause liver injury as assessed by traditional liver chemistries. However, 48 hours after exposure, treated subjects showed marked down-regulation of genes involved in oxidative phosphorylation/mitochondrial function that was not observed in the placebos (P < 1.66E-19). The magnitude of down-regulation was positively correlated with the percent of APAP converted to the reactive metabolite N-acetyl-p-benzoquinone-imide (NAPQI) (r= 0.739;P= 0.058). In addition, unbiased analysis of the serum metabolome revealed an increase in serum lactate from 24 to 72 hours postdosing in the treated subjects alone (P< 0.005). Similar PB transcriptome changes were observed in human overdose patients and rats receiving toxic doses.
The single 4-g APAP dose produced a transcriptome signature in PB cells characterized by down-regulation of oxidative phosphorylation genes accompanied by increased serum lactate. Similar gene expression changes were observed in rats and several patients after consuming hepatotoxic doses of APAP. The timing of the changes and the correlation with NAPQI production are consistent with mechanisms known to underlie APAP hepatoxicity. These studies support the further exploration of the blood transcriptome for biomarkers of DILI.
药物性肝损伤（DILI）的诊断和处理受到传统临床化学方法的限制。最近的研究表明，肝毒物可在啮齿动物的外周血（PB）转录组中产生特定化合物的变化，这表明血液转录组可能为 DILI 提供新的生物标志物。为了在人类中进行研究，我们使用 DNA 微阵列和血清代谢组学方法来描述从六名接受 4 克扑热息痛（APAP）推注剂量的健康成年人和三名接受安慰剂的成年人连续 PB 样本中转录组和代谢组的变化。通过传统的肝功能化学测定，治疗并未引起肝损伤。然而，暴露后 48 小时，与安慰剂相比，治疗组的受试者表现出参与氧化磷酸化/线粒体功能的基因明显下调（P < 1.66E-19）。下调的幅度与 APAP 转化为反应性代谢物 N-乙酰-p-苯醌亚胺（NAPQI）的百分比呈正相关（r= 0.739；P= 0.058）。此外，对血清代谢组的无偏分析显示，仅在治疗组中，血清乳酸从给药后 24 小时到 72 小时增加（P < 0.005）。在人类过量用药患者和接受有毒剂量的大鼠中也观察到类似的 PB 转录组变化。
单次 4 克 APAP 剂量在外周血细胞中产生了转录组特征，其特征是氧化磷酸化基因下调，同时血清乳酸增加。在大鼠和一些服用 APAP 肝毒性剂量的患者中观察到相似的基因表达变化。变化的时间和与 NAPQI 生成的相关性与已知的 APAP 肝毒性机制一致。这些研究支持进一步探索血液转录组以寻找 DILI 的生物标志物。
