Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht, The Netherlands.
Toxicol Appl Pharmacol. 2012 Mar 15;259(3):320-8. doi: 10.1016/j.taap.2012.01.009. Epub 2012 Jan 20.
Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2g dose) and oxidative stress responses (4g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites.
对乙酰氨基酚是欧洲/美国急性肝毒性的主要原因，这导致 FDA 重新考虑有关安全对乙酰氨基酚剂量/用途的建议。不幸的是，目前用于肝毒性的检测方法并不是理想的肝损伤预测标志物，即它们仅在严重肝毒性已经发生后测量对乙酰氨基酚的暴露量。此外，这些检测方法不能提供机制信息。在这里，“组学”技术（代谢组学/基因表达反应的全面分析）可能提供额外的见解。为了更好地了解低剂量对乙酰氨基酚引起的反应，我们评估了（亚）治疗剂量对乙酰氨基酚对健康人类志愿者血液/尿液样本中代谢产物形成和全基因组人类 miRNA 表达变化（包括首次全基因组人类 miRNA 表达变化）的影响。检测到许多已知和几个新的对乙酰氨基酚代谢物，特别是与肝毒性相关的对乙酰氨基酚氧化代谢有关。转录组变化表明免疫调节作用（2g 剂量）和氧化应激反应（4g 剂量）。首次考虑了对乙酰氨基酚对全基因组人类 miRNA 表达的影响，并证实了 mRNA 水平的发现。“组学”技术优于临床化学检测，并揭示了人类对乙酰氨基酚的新反应途径。尽管不能从这项研究中得出关于对乙酰氨基酚潜在免疫毒性作用的明确结论，但有明确迹象表明，即使摄入低剂量的对乙酰氨基酚，免疫系统也会被触发。此外，与高剂量对乙酰氨基酚暴露后相似的氧化应激相关基因反应表明，可能发生治疗剂量对乙酰氨基酚的潜在毒性前作用。可能这些作用与与肝毒性相关的代谢物水平的剂量依赖性增加有关。
