Abstract
Liver damage induced by drug toxicity is an important concern for both medical doctors and patients. The aim of this study was to noninvasively visualize acute liver damage using positron emission tomography (PET) with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[18F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ([18F]FEDAC), a radiotracer specific for translocator protein (18 kDa, TSPO) as a biomarker for inflammation, and to determine cellular sources enriching TSPO expression in the liver. A mild acute liver damage model was prepared by a single intraperitoneal injection of cycloheximide (CHX) into rats. Treatment with CHX induced apoptosis and necrotic changes in hepatocytes with slight neutrophil infiltration. The uptake of radioactivity in the rat livers was measured with PET after injection of [18F]FEDAC. The uptake of [18F]FEDAC increased in livers damaged from treatment with CHX compared to the controls. Presence of TSPO was examined in the liver tissue using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical assays. mRNA expression of TSPO was elevated in the damaged livers compared to the controls, and the level was correlated with the [18F]FEDAC uptake and severity of damage. TSPO expression in the damaged liver sections was mainly found in macrophages (Kupffer cells) and neutrophils, but not in hepatocytes. The elevation of TSPO mRNA expression was derived from the increase of the number of macrophages with TSPO and neutrophils with TSPO in damaged livers. From this study we considered that PET imaging with [18F]FEDAC represented the mild liver damage through the enhanced TSPO signal in inflammatory cells. We conclude that this method may be a useful tool for diagnosis in early stage of acute liver damage.
Highlights
Medical drugs and their metabolites are believed to have caused liver dysfunction in many cases [1]
Because of the limitations of liver biopsy and the currently available noninvasive imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), new noninvasive modalities that accurately and rapidly distinguish liver damage and assess damage severity have become a requirement in hepatology [5]
The remaining liver samples were stored at -80uC for quantitative reversetranscription polymerase chain reaction assay and immunohistochemical examination
Summary
Medical drugs and their metabolites are believed to have caused liver dysfunction in many cases [1]. Jaundice appears in cholestatic liver disease; accurate symptoms in real-time are not easy to observe in cases of hepatocellular injury-type drug-induced liver damage. Because of the limitations of liver biopsy and the currently available noninvasive imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), new noninvasive modalities that accurately and rapidly distinguish liver damage and assess damage severity have become a requirement in hepatology [5]. Compared to serum tests and histological assessments, positron emission tomography (PET) imaging with a specific radiotracer enables direct, quantitative, and multispatial visualization of physiological and cellular processes at multiple time points and at the macroscopic level [6]
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