This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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-wisecorrelation. 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 bereadmitted 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.
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