M1 muscarinic receptors modify oxidative stress response to acetaminophen-induced acute liver injury |
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| Institution: | 1. Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;2. Division of Gastroenterology and Hepatology, Georgia Regents University, Augusta, GA 30912, USA;3. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;4. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA;5. Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;1. Digestive Surgery Unit, Hopital Erasme, Brussels, Belgium;2. Laboratory of Experimental Medicine, Université Libre de Bruxelles, Centre Hospitalier Universitaire, Brugmann site Horta, Brussels, Belgium;3. Neurophysiology Department, People Friendship University, Moscow, Russian Federation;4. Central Institute of Emergencies, Moscow, Russian Federation;5. Institut de Pathologie et de Génétique, Gosselies, Belgium;1. Department of Otolaryngology, University of Rochester School of Medicine and Dentistry, Rochester, New York;2. Department of Pathology, University of Rochester School of Medicine and Dentistry, Rochester, New York;3. Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York;4. Center for Oral Biology, Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York;1. College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China;2. College of Biological Science and Engineering, Shaanxi University of Technology, Hanzhong 723000, China;3. Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany;1. Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China;2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China |
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| Abstract: | The role of muscarinic receptor subtypes in modulating acute liver injury is unknown. We detected M1 muscarinic receptor (M1R) expression in human and murine hepatocytes, and investigated the consequences of M1R deficiency on acute liver injury in vivo and inhibiting M1R activation on hepatocyte injury in vitro. Age-matched wild-type (WT) and M1R-deficient (Chrm1?/?) male mice were injected intraperitoneally with 200 mg/kg acetaminophen (APAP) and euthanized 0, 2, 4, 16, 24, and 36 h later. Biochemical and histological parameters indicated that liver injury peaked within 16 h after APAP treatment and resolved by 24 h. Compared to WT, M1R-deficient mice had reduced intrahepatic hemorrhage and hepatocyte necrosis, reflected by an attenuated rise in serum alanine aminotransferase levels. Livers of M1R-deficient mice showed reduced hepatocyte DNA fragmentation and attenuated expression of injury cytokines (Il-1α, Il-1β, Il-6, and Fasl). In all mice hepatic glutathione levels decreased after APAP injection, but they recovered more quickly in M1R-deficient mice. During the course of APAP-induced liver injury in M1R-deficient compared to WT mice, hepatic Nrf-2, Gclc, and Nqo1 expressions increased and nitrotyrosine generation decreased. APAP metabolic pathways were not altered by M1R deficiency; expression of hepatic Cyp2e1, Cyp1a2, Cyp3a11, Cyp3a13, Car, and Pxr was similar in Chrm1?/? and WT mice. Finally, treatment of murine AML12 hepatocytes with a novel M1R antagonist, VU0255035, attenuated H2O2-induced oxidative stress, prevented GSH depletion, and enhanced viability. We conclude that M1R modify hepatocyte responses to oxidative stress and that targeting M1R has therapeutic potential for toxic liver injury. |
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| Keywords: | Acetaminophen Muscarinic receptors Liver Oxidative stress G protein-coupled receptors |
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