Visualization of acute liver damage induced by cycloheximide in rats using PET with [(18)F]FEDAC, a radiotracer for translocator protein (18 kDa).
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-[(18)F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ([(18)F]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 [(18)F]FEDAC. The uptake of [(18)F]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 [(18)F]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 [(18)F]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.
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Akiko
A
Hatori
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Joji
J
Yui
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Lin
L
Xie
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Tomoteru
T
Yamasaki
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Katsushi
K
Kumata
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Masayuki
M
Fujinaga
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Hidekatsu
H
Wakizaka
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Masanao
M
Ogawa
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Nobuki
N
Nengaki
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Kazunori
K
Kawamura
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Ming-Rong
MR
Zhang
D000081:Acetamides / Q000493:pharmacokinetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D003513:Cycloheximide / Q000633:toxicity*; D007124:Immunoenzyme Techniques; D008297:Male; D049268:Positron-Emission Tomography; D011500:Protein Synthesis Inhibitors / Q000633:toxicity; D021381:Protein Transport; D011687:Purines / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000235:genetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution
D000081:Acetamides; D002352:Carrier Proteins; C578604:N-benzyl-N-methyl-2-(7,8-dihydro-7-(2-fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D011500:Protein Synthesis Inhibitors; D011687:Purines; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D003513:Cycloheximide