TOXICOGENOMICS OF ACETAMINOPHEN HEPATOTOXICITY- RECHALLENGE PROTOCOL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：在本研究中，10名符合条件的正常健康志愿者(男5名，女5名)在过去6个月内没有接触过对乙酰氨基酚，将被送入GCRC并给予对乙酰氨基酚(APAP：1g Q6H，连续10天)。然后，在家中避免APAP两周后，这些受试者将再次入院并再次接受挑战(Q6H 1g，为期10天)。在每个10天的挑战中，关注的结果是从基线观察到的下列反应的最大变化：(1)血清log10ALT和其他相关肝酶，(2)外周血转录组指示的基因表达，(3)血浆代谢组谱，(4)尿代谢组谱。 这项研究的主要目的是评估配对(挑战和再挑战)肝酶反应之间的相关性。预期的结果是，受试者S对复试的ALT反应将与他/她最初的挑战反应相似，从而产生高配对 相关性。这项研究的次要目的是探索转录和代谢数据所表明的生理反应。 对象：健康受试者10人，男5人，女5人。 程序：受试者将在GCRC住院11天，在第一天，他们将开始服用对乙酰氨基酚。将在整个方案中采集血液样本，以监测安全性和进行研究分析。一旦出院，受试者将等待14天，然后 再次入院的学习程序与首次入院时相同。第二次入院出院后14天将进行随访，届时研究将完成。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Purpose: In this study, N=10 eligible normal healthy volunteers (5 men, 5 women) who have not been exposed to acetaminophen in the past six months will be admitted to the GCRC and challenged with acetaminophen (APAP: 1g Q6H for 10days). Then after avoiding APAP at home for two weeks these subjects will be re-admitted and re-challenged (1g Q6H for 10days). The outcomes of interest during each 10-day challenge are the maximum observed changes from baseline for the following responses: (1) serum log10ALT and other related liver enzymes, (2) gene expression indicated by peripheral blood transcriptome, (3) plasma metabolome profile, (4) urine metabolome profile. The primary aim of the study is to evaluate correlation between the paired (challenge vs. rechallenge)liver enzyme responses. The expected result is that the subject s ALT response to rechallenge will be similar to his/her initial challenge response, thus yielding a high pair-wise correlation. The secondary aims of the study are to explore physiologic responses indicated by the transcriptomic and metabolomic data. Participants: Ten healthy subjects, five males and five females. Procedures: Subjects will be admitted to the GCRC for 11 days and on day 1, they will begin dosing with acetaminophen. Blood samples will be taken throughout the protocol to monitor for safety and for research analyses. Once discharged, subjects will wait 14 days and then be readmitted for identical study procedures as the first admission. There will be a followup visit at 14 days after discharge from the second admission and the study will then be completed.