Effect of methionine and choline on liver tumor promotion by phenobarbital and DDT in diethylnitrosamine-initiated rats

Shivapurkar, Narayan; Hoover, Karen L.; Poirier, Lionel A.

doi:10.1093/carcin/7.4.547

Cited by 28 publications

(13 citation statements)

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“…This could be partly attributed to an induction in the expression of MAT2A, which along with the fall in SAMe, has been shown by others to be necessary for hepatocyte proliferation to occur (10)(11)(12)22). A potential mechanism for this is the ability of SAMe to modulate the activity of HGF.…”

Section: Discussionmentioning

confidence: 94%

Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A

et al. 2004

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Methionine adenosyltransferase (MAT) is an essential enzyme because it catalyzes the formation of S-adenosylmethionine (SAMe), the principal biological methyl donor. Of the two genes that encode MAT, MAT1A is mainly expressed in adult liver and MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic SAMe content and spontaneously develop hepatocellular carcinoma. The current study examined the influence of chronic hepatic SAMe deficiency on liver regeneration. Despite having higher baseline hepatic staining for proliferating cell nuclear antigen, MAT1A knockout mice had impaired liver regeneration after partial hepatectomy (PH) as determined by bromodeoxyuridine incorporation. This can be explained by an inability to up-regulate cyclin D1 after PH in the knockout mice. Upstream signaling pathways involved in cyclin D1 activation include nuclear factor κB (NFκB), the c-Jun-N-terminal kinase (JNK), extracellular signal-regulated kinases (ERKs), and signal transducer and activator of transcription-3 (STAT-3). At baseline, JNK and ERK are more activated in the knockouts whereas NFκB and STAT-3 are similar to wild-type mice. Following PH, early activation of these pathways occurred, but although they remained increased in wildtype mice, c-jun and ERK phosphorylation fell progressively in the knockouts. Hepatic SAMe levels fell progressively following PH in wild-type mice but remained unchanged in the knockouts. In culture, MAT1A knockout hepatocytes have higher baseline DNA synthesis but failed to respond to the mitogenic effect of hepatocyte growth factor. Taken together, our findings define a critical role for SAMe in ERK signaling and cyclin D1 regulation during regeneration and suggest chronic hepatic SAMe depletion results in loss of responsiveness to mitogenic signals. ethionine is an essential amino acid metabolized mainly by the liver, where it is converted, by the enzyme methionine adenosyltransferase (MAT), into Sadenosylmethionine (SAMe), the main biological methyl donor, precursor for polyamines and GSH (1). About 50% of methionine metabolism and up to 85% of all methylation reactions occur in the liver (2). In mammals, there are two genes encoding MAT isoenzymes: MAT I/III are gene products of MAT1A, and MAT II is the gene product of MAT2A. Whereas MAT1A is expressed mainly in the adult liver and is a marker for differentiated liver, MAT2A is expressed in all tissues, including fetal liver, hepatocellular carcinoma (HCC), and, in small quantities, in the adult liver (2). MAT2A is up-regulated during rapid liver growth and dedifferentiation (2). Due to differences in the regulatory and kinetic properties of the various MATs, MAT II cannot maintain the same high levels of SAMe as compared with the combination of MAT I and MAT III (2). Consequently, in MAT1A knockout mice, despite a significant increase in MAT2A expression, the liver content of SAMe is reduced about threefold from birth, when the switch from MAT2A and MAT1A normally takes place (3).It has long been re...

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Section: Discussionmentioning

confidence: 94%

Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A

et al. 2004

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“…83 Our 2-week study may be considered the assessment of the initiation phase, 12 weeks as premalignant phase and 24 weeks as late premalignant transformation phase of hepatocarcinogenesis with subsequent hepatocellular carcinoma development according to previous reports. [84][85][86][87] Treatment with nitrosamines or other carcinogens caused an induction of foci, including basophilic and clear cell foci. 88 Foci of cellular alteration represent a localized proliferation of hepatocytes developing under conditions of initiator-promoter administration; an increase in focal cell proliferation comparative to the normal control, nonfocal hepatocytes can be noticed following carcinogen administration.…”

Section: 69mentioning

confidence: 99%

Chemoprevention of Diethylnitrosamine-Initiated and Phenobarbital-Promoted Hepatocarcinogenesis in Rats by Sulfated Polysaccharides and Aqueous Extract of Ulva lactuca

et al. 2015

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Hepatocellular carcinoma (HCC) is one of the common cancers and lethal diseases worldwide. Both oxidative stress and chronic inflammation contribute to the pathogenesis of HCC. Because of limited treatment options and a grave prognosis of HCC, preventive management has been emphasized. The marine macroalgae Ulva lactuca (Ulvaceae) is consumed by humans and livestock because of its nutritional value. Recent studies showed that various extracts of U. lactuca possess antiviral, antiplasmodial, antinephrotoxic, antioxidant, and anti-inflammatory properties. However, very limited information is available on anticancer potential of U. lactuca with no reports on liver cancer chemopreventive efficacy of this marine algae. Accordingly, the present study was initiated to evaluate the possible antihepatocarcinogenic effects and antioxidant mechanisms of action of various U. lactuca extracts against a clinically relevant rodent model of HCC. Initiation of hepatocarcinogenesis was performed in Sprague-Dawley rats by a single injection of dietary carcinogen diethylnitrosamine (DENA, 200 mg/kg, intraperitoneally), followed by promotion with phenobarbital (0.05%) in drinking water. The rats were fed with daily oral dose (50 mg/kg) of polysaccharide sulfate or aqueous extract of U. lactuca for 2, 12, and 24 weeks. At these timepoints, blood samples were taken to measure hepatic injury markers, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, and bilirubin. The liver tissue was harvested for measurement of hepatic oxidative indices, including lipid peroxidation, reduced glutathione, nitric oxide, catalase, superoxide dismutase, glutathione reductase, and glutathione S-transferase. Hepatic histopathology, immunohistochemical analysis of cell proliferation and apoptosis by DNA fragmentation assay were performed. Our results clearly indicate that sulfated polysaccharides of U. lactuca exert a marked chemoprevention of DENA-initiated hepatocarcinogenesis through inhibition of abnormal cell proliferation and induction of apoptosis. A modest inhibition rat liver carcinogenesis was observed with the aqueous extract. The sulfated polysaccharides altered serum parameters of hepatic damage and modulated various components of the hepatic enzymatic and nonenzymatic antioxidant defense systems. The sulfated polysaccharides from U. lactuca may have unique properties of providing protection against DENAinduced oxidative stress which could contribute to chemoprevention of experimental hepatocarcinogenesis. U. lactuca sulfated polysaccharides could be developed as chemopreventive and therapeutic drug against human HCC.

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“…The study involves evaluation of liver MT expression by scoring MT-immunopositive cells, and determination of hepatic levels of Zn and Cu during the progression of hepatocarcinogenesis through premalignant, late premalignant, and malignant/neoplastic transformation phases (i.e., 16, 24, and 32 weeks of the experimental protocol respectively) of HCC development (Preat et al, 1986;Shivapurkar et al, 1986;Williams et al, 1993;Kolaja et al, 1996). We have focused here on the correlation, first on MT expression and Ki-67-/BrdU-labeling index (KI/BrdU-LI); and second, between MT levels and hepatic levels Zn and Cu with respect to the degree of histological differentiation of liver tumors or tumor stage.…”

Section: Introductionmentioning

confidence: 99%