Effects of DMSO on gene expression in human and rat hepatocytes

Sumida, Kayo; Igarashi, Yoshinobu; Toritsuka, Naoki; Matsushita, Tomochika; Abe-Tomizawa, Kaori; Aoki, Mikio; Urushidani, Tetsuro; Yamada, Hiroshi; Ohno, Yasuo

doi:10.1177/0960327111399325

Cited by 55 publications

(35 citation statements)

References 13 publications

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“…Proposedly, DMSO exerts its differentiating actions by inducing cessation of the cell cycle and hyperacetylation of histones. In addition, DMSO is an inducer of several phase I, II and III drug metabolizing enzymes in hepatocytes including CYP3A4 [26]. On the other hand, DMSO represses various other hepatic functions ( e.g.…”

Section: Discussionmentioning

confidence: 99%

Liver Progenitor Cell Line HepaRG Differentiated in a Bioartificial Liver Effectively Supplies Liver Support to Rats with Acute Liver Failure

et al. 2012

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A major roadblock to the application of bioartificial livers is the need for a human liver cell line that displays a high and broad level of hepatic functionality. The human bipotent liver progenitor cell line HepaRG is a promising candidate in this respect, for its potential to differentiate into hepatocytes and bile duct cells. Metabolism and synthesis of HepaRG monolayer cultures is relatively high and their drug metabolism can be enhanced upon treatment with 2% dimethyl sulfoxide (DMSO). However, their potential for bioartificial liver application has not been assessed so far. Therefore, HepaRG cells were cultured in the Academic Medical Center bioartificial liver (AMC-BAL) with and without DMSO and assessed for their hepatic functionality in vitro and in a rat model of acute liver failure. HepaRG-AMC-BALs cultured without DMSO eliminated ammonia and lactate, and produced apolipoprotein A-1 at rates comparable to freshly isolated hepatocytes. Cytochrome P450 3A4 transcript levels and activity were high with 88% and 37%, respectively, of the level of hepatocytes. DMSO treatment of HepaRG-AMC-BALs reduced the cell population and the abovementioned functions drastically. Therefore, solely HepaRG-AMC-BALs cultured without DMSO were tested for efficacy in rats with acute liver failure (n = 6). HepaRG-AMC-BAL treatment increased survival time of acute liver failure rats ∼50% compared to acellular-BAL treatment. Moreover, HepaRG-AMC-BAL treatment decreased the progression of hepatic encephalopathy, kidney failure, and ammonia accumulation. These results demonstrate that the HepaRG-AMC-BAL is a promising bioartificial liver for clinical application.

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Section: Discussionmentioning

confidence: 99%

Liver Progenitor Cell Line HepaRG Differentiated in a Bioartificial Liver Effectively Supplies Liver Support to Rats with Acute Liver Failure

et al. 2012

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“…Microarray analyses assessing the response of S. cerevisiae to DMSO (Zhang et al, 2003) did not identify any genes described in this study, however, correlation between transcriptional events and genes required for growth under a selective condition is often low (Giaever et al, 2002). The requirement of COG and SNARE Golgi/ER genes for DMSO tolerance (Figure 1) may reflect findings in human and rat hepatocytes, where DMSO altered expression of genes associated with SNARE interactions in vesicular transport (Sumida et al, 2011). Furthermore, as a “chemical chaperone,” DMSO can mimic the function of molecular chaperones (Papp and Csermely, 2006), a group of proteins closely tied to Golgi/ER operations.…”

Section: Discussionmentioning

confidence: 66%

“…DMSO could conceivably cause DNA damage, as demonstrated by DNA repair mutant sensitivity (Figure 4A). DMSO damaged DNA in bull sperm (Taşdemir et al, 2013) and erythroleukemic cells (Scher and Friend, 1978), and additionally altered expression of DNA repair genes in human and rat hepatocytes (Sumida et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Functional genomics indicates yeast requires Golgi/ER transport, chromatin remodeling, and DNA repair for low dose DMSO tolerance

Gaytán¹,

Loguinov²,

Rosa³

et al. 2013

Front. Genet.

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Dimethyl sulfoxide (DMSO) is frequently utilized as a solvent in toxicological and pharmaceutical investigations. It is therefore important to establish the cellular and molecular targets of DMSO in order to differentiate its intrinsic effects from those elicited by a compound of interest. We performed a genome-wide functional screen in Saccharomyces cerevisiae to identify deletion mutants exhibiting sensitivity to 1% DMSO, a concentration standard to yeast chemical profiling studies. We report that mutants defective in Golgi/ER transport are sensitive to DMSO, including those lacking components of the conserved oligomeric Golgi (COG) complex. Moreover, strains deleted for members of the SWR1 histone exchange complex are hypersensitive to DMSO, with additional chromatin remodeling mutants displaying a range of growth defects. We also identify DNA repair genes important for DMSO tolerance. Finally, we demonstrate that overexpression of histone H2A.Z, which replaces chromatin-associated histone H2A in a SWR1-catalyzed reaction, confers resistance to DMSO. Many yeast genes described in this study have homologs in more complex organisms, and the data provided is applicable to future investigations into the cellular and molecular mechanisms of DMSO toxicity.

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“…Cryopreserved human hepatocytes were exposed to either 0.5% DMSO (DMSO applied to cryopreserved human hepatocytes is not toxic up to 2% [19]) or Aroclor 1260 (10 μg/mL) for 6 and 24 hours. At each time point cells were stained with Hoechst 33342 (Thermo-Scientific, Waltham, MA) and imaged.…”

Section: Methodsmentioning

confidence: 99%

Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis

Hardesty

Wahlang

Falkner

et al. 2019

Cellular Signalling

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Background: Polychlorinated biphenyl-mediated steatohepatitis has been shown to be due in part to inhibition of epidermal growth factor receptor (EGFR) signalling. EGFR signalling regulates many facets of hepatocyte function, but it is unclear which other kinases and pathways are involved in the development of toxicant-associated steatohepatitis (TASH). Methods: Comparative hepatic phosphoproteomic analysis was used to identify which kinases were affected by either PCB exposure (Aroclor 1260 mixture), high fat diet (HFD), or their interaction in a chronic exposure model of TASH. Cellular assays and western blot analysis were used to validate the phosphoproteomic findings. Results: 1760 unique phosphorylated peptides were identified and of those 588 were significantly different. PCB exposure and dietary interaction promoted a near 25% reduction of hepatic phospho-peptides. Leptin and insulin signalling were pathways highly affected by PCB exposure and liver necrosis was a pathologic ontology over represented due to interaction between PCBs and a HFD. Casein kinase 2 (CK2), Extracellular regulated kinase (ERK), Protein kinase B (AKT), and Cyclin dependent kinase (CDK) activity were demonstrated to be downregulated after PCB exposure and this downregulation was exacerbated with a HFD. PCB exposure led to a loss of hepatic CK2 subunit expression limiting CK2 kinase activity and negatively regulating caspase-3 (CASP3). PCBs promoted secondary necrosis in vitro validating the latter observation. The loss of hepatic phosphoprotein signalling appeared to be due to decreased signal transduction rather than phosphatase upregulation. Conclusions: PCBs are signal disrupting chemicals that promote secondary necrosis through affecting a myriad of liver processes including metabolism and cellular maintenance. PCB exposure, particularly with interaction with a HFD greatly down- regulates the hepatic kinome. More data are needed on signalling disruption and its impact on liver health.

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Effects of DMSO on gene expression in human and rat hepatocytes

Cited by 55 publications

References 13 publications

Liver Progenitor Cell Line HepaRG Differentiated in a Bioartificial Liver Effectively Supplies Liver Support to Rats with Acute Liver Failure

Liver Progenitor Cell Line HepaRG Differentiated in a Bioartificial Liver Effectively Supplies Liver Support to Rats with Acute Liver Failure

Functional genomics indicates yeast requires Golgi/ER transport, chromatin remodeling, and DNA repair for low dose DMSO tolerance

Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis

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