Premium
Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation
Author(s) -
Fannin Rick D.,
Russo Mark,
O'Connell Thomas M.,
Gerrish Kevin,
Winnike Jason H.,
Macdonald Jeffrey,
Newton Jack,
Malik Shahid,
Sieber Stella O.,
Parker Joel,
Shah Ruchir,
Zhou Tong,
Watkins Paul B.,
Paules Richard S.
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23330
Subject(s) - transcriptome , metabolome , metabolite , pharmacology , oxidative phosphorylation , acetaminophen , liver injury , biology , toxicogenomics , drug metabolism , metabolomics , gene expression , endocrinology , biochemistry , drug , gene , bioinformatics
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. Conclusion: 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. (H EPATOLOGY 2010.)