Effect of ethanol on polyamine synthesis during liver regeneration in rats.

Diehl, Anna Mae; Wells, Michael R.; Brown, Nesbitt D.; Thorgeirsson, Snorri S.; Steer, Clifford J.

doi:10.1172/jci114450

Cited by 53 publications

(23 citation statements)

References 38 publications

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“…Nevertheless, our data are consistent with previous reports that showed chronic ethanol-fed rats exhibited diminished liver regeneration. 48 Surprisingly GCS-LS was not induced. The cis-acting elements, AP-1, ARE, and NF-B, implicated in mediating the effect of oxidative stress on GCS subunit gene expression were all activated in this model.…”

Section: Figmentioning

confidence: 93%

Effect of ethanol and high-fat feeding on hepatic γ-glutamylcysteine synthetase subunit expression in the rat

Lu¹,

Huang²,

Yang³

et al. 1999

Hepatology

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Glutathione (GSH) is important in antioxidant defense. A major determinant of the rate of GSH synthesis is the activity of the rate-limiting enzyme, ␥-glutamylcysteine synthetase (GCS). A heavy (HS) and light subunit (LS) make up GCS; oxidative stress regulates both transcriptionally. Cis-acting elements important for the oxidative stressinduced transcriptional up-regulation of both subunits are antioxidant response element (ARE) and activator protein-1 (AP-1). Nuclear factor-B (NF-B) may also regulate the heavy subunit. Chronic ethanol ingestion causes oxidative stress, increases AP-1 expression, and depletes hepatic GSH. Data conflict regarding GSH synthesis and are lacking regarding GCS subunit gene expression. We examined the effect of chronic ethanol ingestion on ARE, AP-1, and NF-B activity and GCS subunit expression. Male Wistar rats were fed an ethanol and high-fat (28.7% cal) diet intragastrically for 9 weeks. Liver GSH level fell by 40%, although GCS activity doubled. GCS-HS mRNA level doubled, whereas GCS-LS mRNA level remained unchanged. Electrophoretic mobility shift assay (EMSA) showed that binding to ARE, AP-1, and NF-B probes all increased. In conclusion, chronic ethanol ingestion increased GCS-HS expression and GCS activity by activating cis-acting elements important for transcriptional up-regulation of GCS-HS. GCS-LS mRNA level remained unchanged despite activation of ARE and AP-1, suggesting that negative transcriptional factors may be involved or the mRNA may be unstable. Despite induction in GCS activity, GSH level fell because of alterations in the other factors important in determining the steady-state GSH level. (HEPATOLOGY 1999;30:209-214.) Glutathione (GSH) is a tripeptide, ␥-glutamylcysteinylglycine, which defends against toxins and free radicals. 1 The cellular GSH level is determined by a balance of the rate of its synthesis and the rates of its utilization (conjugation) and loss (export). 2 Synthesizing GSH from its constituent amino acids involves two adenosine triphosphate-requiring enzymatic steps: forming ␥-glutamylcysteine from glutamate and cysteine, and forming GSH from ␥-glutamylcysteine and glycine. The rate of GSH synthesis is determined by the availability of cysteine and the activity of the rate-limiting enzyme, ␥-glutamylcysteine synthetase (GCS), which is subject to feedback-competitive inhibition by GSH (K i ϭ 2.3 mmol/L). 1-3 The GCS enzyme is composed of a heavy (Mr ϳ 73,000) and a light (Mr ϳ 30,000) subunit that are encoded for by different genes and dissociate under reducing conditions. 4,5 The heavy subunit (HS) exhibits all of the catalytic activity of the isolated enzyme as well as the feedback inhibition by GSH. 6 The light subunit (LS) is enzymatically inactive but plays an important regulatory function by lowering the K m of GCS for glutamate and raising the K i for GSH. 5,7 Recent studies have shown that both GCS subunits are up-regulated transcriptionally by oxidative stress. 1,[8][9][10][11][12][13] The 5Ј-flanking region of both human GCS subunits ha...

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Section: Figmentioning

confidence: 93%

Effect of ethanol and high-fat feeding on hepatic γ-glutamylcysteine synthetase subunit expression in the rat

Lu¹,

Huang²,

Yang³

et al. 1999

Hepatology

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“…Recovery (gain) of the removed liver mass was calculated according to Diehl et al (1990). All results are expressed as mean Ϯ SE.…”

Section: Calculations and Statisticsmentioning

confidence: 99%

Inhibitory Effect of Vitamin E Administration on the Progression of Liver Regeneration Induced by Partial Hepatectomy in Rats

Trejo-Solís

Sánchez

Aranda‐Fraustro

et al. 2003

Laboratory Investigation

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SUMMARY:We have proposed that controlled peroxidative modifications of membranes could be playing a role in the early steps of liver regeneration. Hence, lipid peroxidation (LP) was modified in vivo by treatment with vitamin E in rats subjected to partial hepatectomy (PH), and its influence on liver regeneration was evaluated. Our results, using several methods to monitor LP, indicate that vitamin E administration promoted a decreased LP rate in liver subcellular membranes. Vitamin E drastically diminished cytosolic LP, shifting earlier increased LP in plasma membranes, and promoted a higher increase of nuclear LP in animals subjected to PH. Pretreatment with vitamin E induced a striking reduction of liver mass recovery and nuclear bromodeoxyuridine labeling (clearly shown at 24 hours after surgery), as well as promoted a decreased expression of cyclin D1 and of the proliferating cell nuclear antigen after PH. These effects seem to lead to a decreased mitotic index at 48 hours after PH. Vitamin E pretreatment also diminished PH-induced hypoglycemia but elevated serum bilirubin level, which was not observed in PH animals without vitamin treatment. In conclusion, an enhanced but controlled LP seems to play a critical role during the early phases of liver regeneration. Decreasing magnitude or time course of the PH-promoted enhanced LP (at early post-PH stages) by in vivo treatment with vitamin E could promote an early termination of preparative cell events, which lead to the replicative phase, during PH-promoted liver proliferation. The latter could have a significant implication in the antitumorigenic effect ascribed to the treatment with vitamin E. (Lab Invest 2003, 83:1669 -1679.

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“…The gain of liver mass as a function of time after surgical resection was calculated as described by Diehl et al (1990). All comparisons were done between means of the PH group and those of PH plus adenosine group using Sigma StatSoftware package version 3.5 for personal computers.…”

Section: Methodsmentioning

confidence: 99%

Adenosine Administration Accelerates Progression of the Cell Cycle during Rat Liver Regeneration Induced by One-Third Hepatectomy

Mendieta-Condado

Pichardo-Olvera²,

Sánchez-Sevilla³

et al. 2009

J Pharmacol Exp Ther

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We have shown that adenosine administration is capable of reversing fibrosis in the carbon tetrachloride-induced rat cirrhotic liver, stimulating the diminished proliferative potential of the cirrhotic liver. To characterize adenosine actions on liver cellular proliferation, we used rats subjected to one-third partial hepatectomy (PH). In PH animals acutely administered with adenosine (25-200 mg/kg b.w.), parameters indicative of cell proliferation were determined. In addition, hepatocyte growth factor (HGF), epidermal growth factor, and transforming growth factor-␣, cyclins, members of the E2F family, proto-oncogenes, and adenosine-receptors were determined through Western blot analyses. Adenosine (100 mg/kg body weight) induced an earlier increase in liver cell proliferation as evidenced by enhanced levels of proliferating cell nuclear antigen, nuclear Ki-67 antigen, and those for cyclins (D1, E, A, and B1), as well as by an increased mitotic index. These effects were also accompanied for a long-lasting increase of serum and liver levels of HGF and liver expression of c-Met and HGF liver activator. Adenosine effects on cell proliferation could be mediated by an early increase in E2F-1 and by that of c-Myc, despite the fact that phosphorylation of the Rb protein and expression of E2F-3 were decreased. Moreover, the liver amount of specific receptors for adenosine was not significantly changed by PH and/or adenosine treatment. In conclusion, these data suggest that adenosine actions can accelerate and increase proliferation in a "primed" liver, mainly through enhancing c-Myc, E2F family, cell-cycle cyclins, and HGF expression. Therefore, these pharmacological adenosine effects suggest a modulating role for the nucleoside on mitogenic events once the liver has been triggered to proliferate.Liver regeneration represents proliferation of highly differentiated cells in order to rapidly reconstitute the original functional mass of the organ even after 70% partial hepatectomy (PH) in rats. During regeneration, liver functions are compromised and limited to the minimum, depending on an equilibrium between the essential functions and the rate of cell proliferation tightly controlled in the remnant liver (Michalopoulos and DeFrances, 1997).The PH has been a useful model to study liver regeneration for many years, given an ordered and synchronized proliferation of hepatic cells and involving various phases of the cell cycle (Michalopoulos and DeFrances, 1997). In rats subjected to PH, it is possible to establish different thresholds of proliferation, proportional to the extent of the removed liver mass. Indeed, one-third PH produces a low proliferative burst, with diverse metabolic changes that differ from the maximum achieved with two-thirds PH (Herná ndez-Muñ oz et López-Valencia et al., 2007), proving useful to assess effects of drugs with presumably stimulatory or inhibitory actions on cell proliferation.We reported previously that adenosine administration (200 mg/kg b.w., administered intraperitoneally three ...

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Effect of ethanol on polyamine synthesis during liver regeneration in rats.

Cited by 53 publications

References 38 publications

Effect of ethanol and high-fat feeding on hepatic γ-glutamylcysteine synthetase subunit expression in the rat

Effect of ethanol and high-fat feeding on hepatic γ-glutamylcysteine synthetase subunit expression in the rat

Inhibitory Effect of Vitamin E Administration on the Progression of Liver Regeneration Induced by Partial Hepatectomy in Rats

Adenosine Administration Accelerates Progression of the Cell Cycle during Rat Liver Regeneration Induced by One-Third Hepatectomy

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