Impaired mitochondrial function in HepG2 cells treated with hydroxy-cobalamin[c-lactam]: A cell model for idiosyncratic toxicity

Haegler, Patrizia; Grünig, David; Berger, Benjamin; Krähenbühl, Stephan; Bouitbir, Jamal

doi:10.1016/j.tox.2015.07.015

Cited by 11 publications

(10 citation statements)

References 33 publications

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“…However, we were surprised to find no significant changes in mitochondrial superoxide accumulation. In contrast to the current findings, we have shown recently that treatment of HepG2 cells with HCCL is associated with increased mitochondrial ROS production [ 38 ]. One explanation for these divergences could be the absence of specific mitochondrial substrates (i.e.…”

Section: Discussioncontrasting

confidence: 99%

“…Second, one of our goals was to create a simple, reproducible model of a hepatic mitochondrial disease in mice. We planned to use this model for toxicological studies of established or suspected mitochondrial toxicants, since underlying mitochondrial diseases can aggravate cellular and/or organ toxicity of mitochondrial toxicants [ 18 – 20 ]. Furthermore, we also wanted to study the consequences of the expected impairment of the mitochondrial respiratory chain on hepatic function and morphology in more detail.…”

Section: Introductionmentioning

confidence: 99%

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Hepatic Effects of Pharmacological Doses of Hydroxy-Cobalamin[c-lactam] in Mice

et al. 2017

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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.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hepatic Effects of Pharmacological Doses of Hydroxy-Cobalamin[c-lactam] in Mice

et al. 2017

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“…Although it is effective, serious incidents of BBR-induced idiosyncratic hepatotoxicity including some fatalities have been reported. BBR was reported to induce impairment of oxidative phosphorylation in cultured HepG2 cells (Haegler et al, 2015). Arai et al (2002) speculated that administration of allopurinol (xanthine oxidase enzyme inhibitor) with BBR may accelerate the occurrence of liver dysfunction.…”

Section: Downloaded Frommentioning

confidence: 99%

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

Wang

Peng

et al. 2016

Drug Metabolism and Disposition

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Benzbromarone (BBR) is a benzofuran derivative that has been quite useful for the treatment of gout; however, it was withdrawn from European markets in 2003 because of reported serious incidents of drug-induced liver injury. BBR-induced hepatotoxicity has been suggested to be associated with the formation of a quinone intermediate. The present study reported epoxide-derived intermediate(s) of BBR. An N-acetylcysteine (NAC) conjugate derived from epoxide metabolite(s) was detected in both microsomal incubations of BBR and urine samples of mice treated with BBR. The NAC conjugate was identified as 6-NAC BBR. Ketoconazole suppressed the bioactivation of BBR to the epoxide intermediate(s), and the CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s). The present study provided new information on metabolic activation of BBR.

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“…Over the last three decades, several studies have been published showing that c -lactam of hydroxycobalamin ( c -lactam OH-Cbl) is an efficient cobalamin antagonist [ 4 , 5 , 6 , 7 , 8 , 9 ]. According to Zelder et al [ 10 ], c -lactam OH-Cbl belongs to class A antivitamins being non-functional structural analogues of vitamin B12 that inhibit the vitamin transportation.…”

Section: Introductionmentioning

confidence: 99%

“…According to Zelder et al [ 10 ], c -lactam OH-Cbl belongs to class A antivitamins being non-functional structural analogues of vitamin B12 that inhibit the vitamin transportation. Indeed, the use of the agent in in vitro [ 6 , 7 , 8 ] experimental models resulted in an inhibition of cobalamin-dependent enzymes and in an increase in the level of cobalamin deficiency biomarkers. Moreover, studies on rats [ 4 , 5 ] also revealed that treatment in vivo with c -lactam OH-Cbl resulted in the rapid development of a severe metabolic defect analogous to vitamin B12 deficiency.…”

Section: Introductionmentioning

confidence: 99%

Astrogliosis in an Experimental Model of Hypovitaminosis B12: A Cellular Basis of Neurological Disorders due to Cobalamin Deficiency

Rzepka

Rok

Kowalska

et al. 2020

Cells

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Cobalamin deficiency affects human physiology with sequelae ranging from mild fatigue to severe neuropsychiatric abnormalities. The cellular and molecular aspects of the nervous system disorders associated with hypovitaminosis B12 remain largely unknown. Growing evidence indicates that astrogliosis is an underlying component of a wide range of neuropathologies. Previously, we developed an in vitro model of cobalamin deficiency in normal human astrocytes (NHA) by culturing the cells with c-lactam of hydroxycobalamin (c-lactam OH-Cbl). We revealed a non-apoptotic activation of caspases (3/7, 8, 9) in cobalamin-deficient NHA, which may suggest astrogliosis. The aim of the current study was to experimentally verify this hypothesis. We indicated an increase in the cellular expression of two astrogliosis markers: glial fibrillary acidic protein and vimentin in cobalamin-deficient NHA using Western blot analysis and immunocytochemistry with confocal laser scanning microscopy. In the next step of the study, we revealed c-lactam OH-Cbl as a potential non-toxic vitamin B12 antagonist in an in vivo model using zebrafish embryos. We believe that the presented results will contribute to a better understanding of the cellular mechanism underlying neurologic pathology due to cobalamin deficiency and will serve as a foundation for further studies.

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Impaired mitochondrial function in HepG2 cells treated with hydroxy-cobalamin[c-lactam]: A cell model for idiosyncratic toxicity

Cited by 11 publications

References 33 publications

Hepatic Effects of Pharmacological Doses of Hydroxy-Cobalamin[c-lactam] in Mice

Hepatic Effects of Pharmacological Doses of Hydroxy-Cobalamin[c-lactam] in Mice

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

Astrogliosis in an Experimental Model of Hypovitaminosis B12: A Cellular Basis of Neurological Disorders due to Cobalamin Deficiency

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