Variations of ornithine decarboxylase activity and S-adenosyl-L-methionine and 5'-methylthioadenosine contents during the development of diethylnitrosamine-induced liver hyperplastic nodules and hepatocellular carcinoma

Garcea, Renato; Pascale, Rosa M.; Daino, Lucia; Frassetto, Serenella; Cozzolino, Patrizia; Ruggiu, Maria E.; Vannini, Maria G.; Gaspa, Leonardo; Feo, Francesco

doi:10.1093/carcin/8.5.653

Cited by 36 publications

(29 citation statements)

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“…Many data in the literature evoke the presence of highly proliferating.cells in preneoplastic lesions in other protocols (Pugh & Goldfarb, 1978;Garcea et al, 1987 It must further be stressed that there is an important interindividual variation between animals receiving the same treatment, so that care must be taken with the summing up of the individual data. In spite of this variation a trend in the reduction to lower C-values can be seen in the merged data.…”

Section: Resultsmentioning

confidence: 99%

Cell population kinetics and ploidy rate of early focal lesions during hepatocarcinogenesis in the rat

Castelain

Deleener²,

Kirsch‐Volders³

et al. 1989

Br J Cancer

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Summary We have studied the changes in cell population kinetics and DNA-content of cycling parenchymal cells during the very early steps of rat hepatocarcinogenesis in Faber's protocol. Adult rats were initiated by a single dose of diethylnitrosamine (DENA, 200 mg kg-1), followed 2 weeks later by a 2-week diet of 0.03% 2-acetylaminofluorene (2-AAF) as selection phase. In the middle of selection time, a single necrogenic dose of carbon tetrachloride (CCL4, 2 ml kg-) was administered by gavage. Twenty four hours thereafter, radiolabelled thymidine (3H-TdR, 1.5 ftCi g' ) was given by repeated injections during 24 h. An emergence of small, pyroninophilic ('tigroid') foci was observed at the second, fifth and eighth days after the proliferative stimulus. The focal putative precancerous cells presented a significant higher labelling index (LI) than the non-affected parenchymal cells for all exposure times. However, the labelling intensity decreased from the second to the eighth day after CC14, suggesting a dilution of the radiolabelled DNA by repeated divisions within the foci. The nuclei of the same foci were analysed for DNA-content by feulgen microdensitometry on neighbouring sections. A gradual reduction of nuclear DNA-content was observed in 66% of the foci at the fifth day and in 100% of foci at the eight day, as compared to surrounding tissue and untreated animals, where labelling and DNA-content remain in the same ratio.

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Section: Resultsmentioning

confidence: 99%

Cell population kinetics and ploidy rate of early focal lesions during hepatocarcinogenesis in the rat

Castelain

Deleener²,

Kirsch‐Volders³

et al. 1989

Br J Cancer

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“…49 In their work, the fall in hepatic SAM level was attributed to increased SAM utilization for polyamine synthesis, which was also induced in the early stages of hepatocarcinogenesis, although whether MAT2A was induced was not examined. 47,48,50 Thus, the fall in SAM is likely the result of a combination of increased utilization and a switch in the MAT expression.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12][13] The activity of MAT is also modulated by SAM, the product of the reaction it catalyzes. SAM strongly inhibits MAT II (IC 50 ϭ 60 µmol/L), whereas it minimally inhibits MAT I (IC 50 ϭ 400 µmol/L) and stimulates MAT III (up to eightfold at 500 µmol/L SAM). 10 In terms of responsiveness to sulfhydryl-modifying agents, the activity of liverspecific MAT is inhibited when certain critical cysteine residues of the enzyme are covalently modified.…”

mentioning

confidence: 99%

Differential Effect of Thioacetamide on Hepatic Methionine Adenosyltransferase Expression in the Rat

Huang¹,

Mato

Kanel

et al. 1999

Hepatology

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Liver-specific and non-liver-specific methionine adenosyltransferase (MAT) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine (SAM), the principal methyl donor. Mature liver expresses mainly MAT1A. We showed a switch from MAT1A to MAT2A gene expression in human liver cancer cells that may offer a growth advantage. To gain a better understanding of the chronology and significance of the change in MAT expression, we examined changes in hepatic MAT expression after acute treatment of rats with a hepatocarcinogen, thioacetamide (TAA). TAA treatment for 3 weeks did not change the MAT1A mRNA level but reduced the liver-specific MAT protein level to below 30% of control. TAA also acutely reduced the activity of liverspecific MAT when added to normal liver homogenates. In contrast, both the mRNA and protein levels of non-liverspecific MAT were induced. Because liver-specific MAT exhibits a much higher Methionine adenosyltransferase (MAT) is a critical cellular enzyme that catalyzes the formation of S-adenosylmethionine (SAM), the principal biological methyl donor and the ultimate source of the propylamine moiety used in polyamine biosynthesis. 1,2 In mammals, two different genes, MAT1A and MAT2A, encode for two homologous MAT catalytic subunits, ␣1 and ␣2. 3-5 MAT1A is expressed only in liver, and it encodes the ␣1 subunit found in two native MAT isozymes, which are either a dimer (MAT III) or tetramer (MAT I) of this single subunit. 5 MAT2A is widely distributed. 3-5 MAT2A also predominates in the fetal liver and is progressively replaced by MAT1A during development. 6,7 MAT2A encodes for a catalytic subunit (␣2) found in a native MAT isozyme (MAT II), which is associated with a catalytically inactive regulatory subunit (␤) in lymphocytes encoded by yet a third unknown gene. 5,8 This regulatory ␤ subunit may be unique to lymphocytes, because it is not found in the kidney. 8 Different isoforms of MAT differ in kinetic and regulatory properties and responsiveness to sulfhydryl agents and dimethyl sulfoxide (DMSO). 2,9-13 The kinetic parameters varied in different studies depending on the purification procedure used and the purity of the enzyme. The K m for methionine is lowest for MAT II (Ϸ4-10 µmol/L), intermediate for MAT I (23 µmol/L-1 mmol/L), and highest for MAT III (215 µmol/L-7 mmol/L), with different studies reporting different absolute values. [9][10][11][12][13] The activity of MAT is also modulated by SAM, the product of the reaction it catalyzes. SAM strongly inhibits MAT II (IC 50 ϭ 60 µmol/L), whereas it minimally inhibits MAT I (IC 50 ϭ 400 µmol/L) and stimulates MAT III (up to eightfold at 500 µmol/L SAM). 10 In terms of responsiveness to sulfhydryl-modifying agents, the activity of liverspecific MAT is inhibited when certain critical cysteine residues of the enzyme are covalently modified. 1,11,[14][15][16] Modifications of these critical cysteine residues can inactivate the enzyme by direct interference with the substrate binding site(s) or by c...

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“…This study was not aimed at evaluating AAF metabolism and formation of DNA adducts in preneoplastic lesions in Wistar rat strain. It should be noted, however, that HCCs develop in 85-90% of Wistar rats initiated by DENA and subjected to promoting treatments based on phenobarbital administration [6,34], and higher AAF concentrations are needed to stimulate selective growth of initiated cells in Wistar rats subjected to RH protocol, with respect to F344 rats [34]. These observations suggest low metabolic activation of AAF in Wistar rats.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence indicates that c-myc functions as a transcription factor that can activate expression of numerous genes involved in liver carcinogenesis including ornithine decarboxylase (ODC) [44] and cell-cycle controlling genes. ODC gene expression, ODC activity, and polyamine level are increased in PNs and HCCs induced by the RH protocol [34,45]. Interestingly, ODC overexpression under the control of strong promoters induces morphological transformation of immortalized NIH/3T3 and Rat-1 fibroblasts [46,47].…”

Section: Discussionmentioning

confidence: 99%

Correlation of c-myc overexpression and amplification with progression of preneoplastic liver lesions to malignancy in the poorly susceptible wistar rat strain

et al. 1999

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Persistent liver nodules (PNs) and hepatocellular carcinomas (HCCs) induced in F344 rats by the resistant hepatocyte (RH) model exhibit c-myc overexpression and amplification. The role of these changes in progression of PN was investigated in nodules with different propensities to evolve to HCC in resistant Wistar rats and, for comparison, in susceptible F344 rats. Initiation of rats with diethylnitrosamine was followed by selection with 2-acetylaminofluorene (AAF) plus partial hepatectomy (RH groups). Two additional Wistar rat groups received a second AAF treatment without (RH+AAF) and with a necrogenic dose of CCl4 (RH+AAF/CCl4) 15 d after selection. The number to liver ratio and volume of glutathione-s-transferase placental form-positive lesions were lower in the Wistar than the F344 RH groups 9 and 32 wk after initiation and increased after a second AAF cycle treatment with and without CCl4. DNA synthesis in glutathione-s-transferase placental form-positive lesions was low in Wistar RH group at 9 wk and was stimulated by additional AAF treatments. HCCs developed at 57-60 wk in F344 RH, Wistar RH+AAF, and RH+AAF/CCl4 rats. Tumor incidence and multiplicity were lower in RH+AAF rats than in RH+AAF/CCl4 and F344 rats. At 32 wk, PN exhibited c-myc overexpression that increased from RH to RH+AAF rats and to RH+AAF/CCl4 Wistar rats. This was associated with c-myc amplification in Wistar RH+AAF/CCl4 rats. These results showed correlation of c-myc overexpression and amplification with nodule propensity to progress to HCC in poorly susceptible Wistar rats and suggested a possible genetic mechanism for susceptibility to hepatocarcinogenesis. The experimental system used in this work may be a valuable tool for studies on molecular mechanisms underlying liver growth and tumorigenesis supported by c-myc overexpression.

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Variations of ornithine decarboxylase activity and S-adenosyl-L-methionine and 5'-methylthioadenosine contents during the development of diethylnitrosamine-induced liver hyperplastic nodules and hepatocellular carcinoma

Cited by 36 publications

References 0 publications

Cell population kinetics and ploidy rate of early focal lesions during hepatocarcinogenesis in the rat

Cell population kinetics and ploidy rate of early focal lesions during hepatocarcinogenesis in the rat

Differential Effect of Thioacetamide on Hepatic Methionine Adenosyltransferase Expression in the Rat

Correlation of c-myc overexpression and amplification with progression of preneoplastic liver lesions to malignancy in the poorly susceptible wistar rat strain

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