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Blood Gene Expression Profiling of an Early Acetaminophen Response (I)

ABSTRACT: Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing and 12 genes were detected with expression profiles significantly altered within 24hrs. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70784 | GEO | 2016/02/16

SECONDARY ACCESSION(S): PRJNA289531

REPOSITORIES: GEO

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Blood Gene Expression Profiling of an Early Acetaminophen Response (II)

2016-02-16 | GSE70786 | GEO

Blood Gene Expression Profiling of an Early Acetaminophen Response (II)

Project description:Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing and 12 genes were detected with expression profiles significantly altered within 24hrs. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration. Overdosed patients admitted to the emergency room. Five male and female individuals from 19 - 59 years old were admitted to the emergency room following an overdose on acetaminophen. The patients presented 12hrs to 4 days after ingestion. ALT and AST elevated peaking beyond 400 U/I and 120 U/I. Blood was collected 2 or 5 days following ingestion.

2016-02-16 | E-GEOD-70786 | biostudies-arrayexpress

Blood Gene Expression Profiling of an Early Acetaminophen Response (I)

Project description:Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing and 12 genes were detected with expression profiles significantly altered within 24hrs. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration. Randomized, single-blind, placebo-controlled, clinical study. Healthy male and female individuals from 18 â 58 years old weighing 55 kg to 85 kg volunteered as subjects in the study. Subjects were enrolled for 14 days each and were acclimated for 3 days on a controlled, standardized whole-food diet in order to assure a uniform nutritional intake. Starting on day 0 and until day 7 relative to the start of dosing, each subject received daily repeat dosing every 6 hrs (i.e. 4x daily) of either 1g of acetaminophen or placebo pills orally. Blood was collected at 8 a.m. on each day of the clinical study for alanine aminotransferase (ALT) measurement and complete blood counts (CBC).

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Homo sapiens

Project description:Circulating miRNAs of acetaminophen-overdosed patients

| PRJNA255643 | ENA

Protein S-nitrosylation Restricts Xenobiotic Receptor PXR Hyperactivity and Ameliorates Acetaminophen-induced Liver Injury in Mice

Project description:Drug-induced liver injury (DILI), especially acetaminophen overdose, is the leading cause of acute liver failure. Pregnane X receptor (PXR) is a nuclear receptor and the master regulator of drug metabolism. Aberrant activation of PXR plays a pathogenic role in the acetaminophen hepatotoxicity. Here, we aimed to examine the PXR S-nitrosylation (SNO) in response to acetaminophen. We found that PXR was S-nitrosylated in hepatocytes and the mouse livers after exposure to acetaminophen or S-nitrosoglutathione (GSNO). Mass-spectrometry and site-directed mutagenesis identified the cysteine 307 as the primary residue for SNO-modification. In hepatocytes, SNO suppressed both agonist (rifampicin and SR12813)-induced and constitutively active PXR (VP-PXR) activations. Furthermore, in acetaminophen overdosed mouse livers, PXR protein was decreased at the centrilobular regions overlapping with increased SNO. In PXR-deficient (PXR-/-) mice, replenishing the livers with the SNO-deficient PXR significantly aggravated hepatic necrosis and apoptosis, increased HMGB1 release, and exacerbated liver injury and inflammation. Particularly, we demonstrated that S-nitrosoglutathione reductase (GSNOR) inhibitor N6022 promoted hepatoprotection by increasing the levels of PXR S-nitrosylation. In conclusion, PXR is post-translationally modified by S-nitrosylation in hepatocytes in response to acetaminophen. This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a new target for therapeutical intervention.

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Project description:Acetaminophen is the primary cause of acute liver toxicity in Europe/USA. Therefore, the FDA reconsiders recommendations concerning safe acetaminophen dosage/use. Current tests for liver toxicity are no ideal predictive markers for liver injury. Here, ‘omics techniques (global analysis of metabolomic/gene expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low dose, we evaluated effects of (sub-)therapeutic acetaminophen doses on metabolite formation/global gene-expression changes (including, for the first time, miRNA) in blood/urine samples from healthy human volunteers.

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Acetaminophen overdose reveals protease activated receptor 4 as a low expressing but potent receptor on the hepatic endothelium in mice

Project description:There is a paucity of data on how protease-activated receptors (PARs) regulate transcriptional reprogramming. We sought to determine how the expression of two members of the PAR family (PAR1 and PAR4) on hepatic endothelial cells (ECs) influence transcription in the liver after acetaminophen (APAP) overdose. We combined EC-specific translating ribosome affinity purification with next-generation sequencing (EC-TRAPseq) in endothelial-specific Par1 and Par4 knockout mice. This allowed us to gain an in vivo snapshot of how EC gene expression profiles change with APAP overdose and how the loss of endothelial PARs impacts transcriptional reprogramming in hepatic ECs. This approach also provided a high degree of sensitivity for detecting low-expressing transcripts. We found distinct transcriptional changes in APAP-overdosed ECs between endothelial Par1 and Par4 knockout mice.

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