Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis

Abstract

We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as sensitive diagnostic and prognostic clinical tools for severe liver injury and could be useful for monitoring drug-induced liver injury during drug discovery.hsa-miR-122-5p | hsa-miR-3646-3p | hsa-miR-412 A cetaminophen (APAP) overdose (OD) is the major cause of acute liver failure and death due to analgesics in the developed world (1-3), with over 500 deaths per year in the United States (3, 4). APAP misuse results in over 78,000 emergency department (ED) visits annually, at a cost of more than $86 million/ year (5).Patients who present with a report of APAP ingestion are assessed for treatment with N-acetyl cysteine (NAC) by measuring serum APAP concentrations and liver function tests, including alanine aminotransferase (ALT) activity (4). There are limits to the utility of the current biomarker, ALT, in assessing the status of potentially APAP-poisoned patients. For example, ALT may take greater than 72 h to reach peak activity in blood (6), and elevated ALT activity is not specific for APAP hepatotoxicity. New biomarkers could serve as more sensitive and specific signatures to predict hepatotoxicity following APAP overdose and to distinguish APAP hepatotoxicity from other causes of liver disease. Ideal biomarkers should identify liver damage at an early stage, accelerating appropriate treatment.MicroRNAs (miRNAs) are short (∼22 nt in length) regulatory RNAs that control gene expression posttranscriptionally (7,8). The human genome contains more than 1,000 genes encoding distinct miRNAs whose levels in a biological sample can be quantified with great sensitivity and precision using quantitative real-time PCR (qRT-PCR) (9). Many miRNAs are expressed tissue-specifically or enriched in certain cell types, with the expression pattern providing signatures for the physiological or pathological status of specific cells and tissues (10, 11). Importantly, miRNAs can be exported from cells and are detectable in stable complexes extracellularly, in blood, serum, or plasma (12).There is ample evidence that circulating extracellular miRNAs in blood can serve as biomarkers for internal organ physiology and pathology (11,13,14). Increased levels of miR-122 and miR-192 were found in the plasma of APAP-overdosed (300 mg/kg) mice (15). A number of additional miRNAs (miR-135a, miR-466g, miR-574-5p, and miR-1196) were elevated in the plasma of mice with hi...

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