Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agent
Drug-induced steatohepatitis is considered more serious than drug-induced hepatic steatosis, so that differentiating between the two is crucial in drug development. In addition, early detection of drug-induced steatohepatitis is considered important since recovery is possible with drug withdrawal. H...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-06-01
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| Series: | Toxicology Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214750023001385 |
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| author | Yuka Yoshino Yuta Fujii Kazuhiro Chihara Aya Nakae Jun-ichiro Enmi Yoshichika Yoshioka Izuru Miyawaki |
| author_facet | Yuka Yoshino Yuta Fujii Kazuhiro Chihara Aya Nakae Jun-ichiro Enmi Yoshichika Yoshioka Izuru Miyawaki |
| author_sort | Yuka Yoshino |
| collection | DOAJ |
| description | Drug-induced steatohepatitis is considered more serious than drug-induced hepatic steatosis, so that differentiating between the two is crucial in drug development. In addition, early detection of drug-induced steatohepatitis is considered important since recovery is possible with drug withdrawal. However, no method has been established to differentiate between the two. In the development of drug-induced steatohepatitis, reactive oxygen species (ROS) is excessively generated in the liver. It has been reported that ROS can be monitored with electron spin resonance (ESR) and dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) by using nitroxyl radicals, which are known to participate in various in vivo redox reactions. The decay/reduction rate, which is an index for monitoring nitroxyl radicals, has been reported to be increased in tissues with excessive ROS levels other than liver, but decreased in methionine choline deficient (MCD) diet-induced steatohepatitis with excess ROS. Therefore, looking to differentiate between drug-induced hepatic steatosis and steatohepatitis, we examined whether the reduction rate decreases in steatohepatitis other than the MCD-diet induced disease and whether the decrease could be detected by MRI. We used STAM™ mice in which hepatic steatosis and steatohepatitis developed sequentially under diabetic conditions. 3-carbamoyl-PROXYL (CmP), one of the nitroxyl radicals, was injected intravenously during the MRI procedure and the reduction rate was calculated. The reduction rate was significantly higher in early steatohepatitis than in hepatic steatosis and the control. Excess ROS in early steatohepatitis was detected by an immunohistochemical marker for ROS. Therefore, it was indicated that the increase or decrease in the reduction rate in steatohepatitis differs depending on the model, and early steatohepatitis could be noninvasively differentiated from hepatic steatosis using CmP in MRI. Since the change in direction of the reduction rate in steatohepatitis in clinical studies could be predicted by confirming the reduction rate in preclinical studies, the present method, which can be used consistently in clinical and preclinical studies, warrants consideration as a candidate monitoring method for differentiating between early drug-induced steatohepatitis and hepatic steatosis in drug development. |
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| institution | Directory Open Access Journal |
| issn | 2214-7500 |
| language | English |
| last_indexed | 2025-03-21T14:51:44Z |
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| spelling | doaj.art-d3fe9ac1385942c88e0bb95af9ef75d62024-06-21T07:39:45ZengElsevierToxicology Reports2214-75002024-06-011219Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agentYuka Yoshino0Yuta Fujii1Kazuhiro Chihara2Aya Nakae3Jun-ichiro Enmi4Yoshichika Yoshioka5Izuru Miyawaki6Preclinical Research Unit, Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan; Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita city, Osaka 565-0871, Japan; Corresponding author at: Preclinical Research Unit, Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.Preclinical Research Unit, Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan; Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita city, Osaka 565-0871, JapanPreclinical Research Unit, Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, JapanGraduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita city, Osaka 565-0871, Japan; Center for Information and Neural Networks (CiNet), Osaka University and National Institute of Information and Communications Technology (NICT), 1-4 Yamadaoka, Suita City, Osaka 565-0871, JapanGraduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita city, Osaka 565-0871, Japan; Center for Information and Neural Networks (CiNet), Osaka University and National Institute of Information and Communications Technology (NICT), 1-4 Yamadaoka, Suita City, Osaka 565-0871, JapanGraduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita city, Osaka 565-0871, Japan; Center for Information and Neural Networks (CiNet), Osaka University and National Institute of Information and Communications Technology (NICT), 1-4 Yamadaoka, Suita City, Osaka 565-0871, JapanPreclinical Research Unit, Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, JapanDrug-induced steatohepatitis is considered more serious than drug-induced hepatic steatosis, so that differentiating between the two is crucial in drug development. In addition, early detection of drug-induced steatohepatitis is considered important since recovery is possible with drug withdrawal. However, no method has been established to differentiate between the two. In the development of drug-induced steatohepatitis, reactive oxygen species (ROS) is excessively generated in the liver. It has been reported that ROS can be monitored with electron spin resonance (ESR) and dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) by using nitroxyl radicals, which are known to participate in various in vivo redox reactions. The decay/reduction rate, which is an index for monitoring nitroxyl radicals, has been reported to be increased in tissues with excessive ROS levels other than liver, but decreased in methionine choline deficient (MCD) diet-induced steatohepatitis with excess ROS. Therefore, looking to differentiate between drug-induced hepatic steatosis and steatohepatitis, we examined whether the reduction rate decreases in steatohepatitis other than the MCD-diet induced disease and whether the decrease could be detected by MRI. We used STAM™ mice in which hepatic steatosis and steatohepatitis developed sequentially under diabetic conditions. 3-carbamoyl-PROXYL (CmP), one of the nitroxyl radicals, was injected intravenously during the MRI procedure and the reduction rate was calculated. The reduction rate was significantly higher in early steatohepatitis than in hepatic steatosis and the control. Excess ROS in early steatohepatitis was detected by an immunohistochemical marker for ROS. Therefore, it was indicated that the increase or decrease in the reduction rate in steatohepatitis differs depending on the model, and early steatohepatitis could be noninvasively differentiated from hepatic steatosis using CmP in MRI. Since the change in direction of the reduction rate in steatohepatitis in clinical studies could be predicted by confirming the reduction rate in preclinical studies, the present method, which can be used consistently in clinical and preclinical studies, warrants consideration as a candidate monitoring method for differentiating between early drug-induced steatohepatitis and hepatic steatosis in drug development.http://www.sciencedirect.com/science/article/pii/S2214750023001385SteatohepatitisMagnetic resonance imagingNitroxyl radicalsReactive oxygen species |
| spellingShingle | Yuka Yoshino Yuta Fujii Kazuhiro Chihara Aya Nakae Jun-ichiro Enmi Yoshichika Yoshioka Izuru Miyawaki Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agent Toxicology Reports Steatohepatitis Magnetic resonance imaging Nitroxyl radicals Reactive oxygen species |
| title | Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agent |
| title_full | Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agent |
| title_fullStr | Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agent |
| title_full_unstemmed | Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agent |
| title_short | Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agent |
| title_sort | non invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an mri contrast agent |
| topic | Steatohepatitis Magnetic resonance imaging Nitroxyl radicals Reactive oxygen species |
| url | http://www.sciencedirect.com/science/article/pii/S2214750023001385 |
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