title: Hepatic Effects of Pharmacological Doses of Hydroxy-Cobalamin[c-lactam] in Mice.
abstract: The vitamin B12 analog hydroxy-cobalamin[c-lactam] (HCCL) impairs hepatic mitochondrial protein synthesis and function of the electron transport chain in rats. We aimed to establish an in vivo model for mitochondrial dysfunction in mice, which could be used to investigate hepatotoxicity of mitochondrial toxicants. In a first step, we performed a dose-finding study in mice treated with HCCL 0.4 mg/kg and 4 mg/kg i.p. for two to four weeks. The plasma methylmalonate concentration was strongly increased at 4 mg/kg starting at three weeks of treatment. We subsequently treated mice daily with 4 mg/kg HCCL i.p. for three weeks and characterized liver function and histology as well as liver mitochondrial function. We found an increase in liver weight in HCCL-treated mice, which was paralleled by hepatocellular accumulation of triglycerides. In liver homogenate of HCCL-treated mice, the complex I activity of the electron transport chain was reduced, most likely explaining hepatocellular triglyceride accumulation. The activity of CPT1 was not affected by methylmalonyl-CoA in isolated liver mitochondria. Despite impaired complex I activity, mitochondrial superoxide anion production was not increased and the hepatocellular glutathione (GSH) pool was maintained. Finally, the mitochondrial DNA content was not altered with HCCL treatment. In conclusion, treatment of mice with HCCL is associated with increased liver weight explained by hepatocellular triglyceride accumulation. Hepatocellular fat accumulation is most likely a consequence of impaired activity of the mitochondrial electron transport chain. The impairment of complex I activity is not strong enough to result in ROS accumulation and reduction of the GSH stores.
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Haegler
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Grünig
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Berger
authors.affiliation: Swiss Center of Applied Human Toxicology, SCAHT, Basel, Switzerland.|Department of Molecular Pathology, Institute for Pathology, University Hospital, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.|Swiss Center of Applied Human Toxicology, SCAHT, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.|Swiss Center of Applied Human Toxicology, SCAHT, Basel, Switzerland.
authors.forename: Jamal
authors.identifier: http://orcid.org/0000-0003-4453-9457
authors.initials: J
authors.lastname: Bouitbir
mesh_terms: D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007769:Lactams / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D014805:Vitamin B 12 / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D007769:Lactams; C071541:hydroxycobalamin(c-lactam); D002334:Carnitine O-Palmitoyltransferase; D014805:Vitamin B 12