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F Feo

Publications and source records attributed to F Feo.

At least 19 recordsLinked to original sources
PubMed1992

Chemoprevention of rat liver carcinogenesis by S-adenosyl-L-methionine: a long-term study.

Previous work has shown a consistent fall in S-adenosyl-L-methionine (SAM) in the liver of diethylnitrosamine-initiated rats, during the development of preneoplastic lesions, in persistent nodules (PNs), and hepatocellular carcinomas. The injection of SAM into rats causes the reconstitution of the SAM pool, coupled with growth restraint, remodeling, and apoptosis of preneoplastic cells, and inhibits the development of PNs and hepatocellular carcinomas. To evaluate if SAM treatment causes a long-term prevention of preneoplastic and neoplastic liver lesions or merely causes a delay in their development, we evaluated the effect of a relatively short SAM treatment on the development of preneoplastic and neoplastic lesions in a long-term study. Male Wistar rats were subjected to initiation with diethylnitrosamine, followed by selection and then by the administration of phenobarbital for 16 weeks. After selection, the rats were given i.m. injections of a purified SAM preparation (384 mumol/kg/day) for 24 weeks. In SAM-treated rats, a decrease in the incidence of PNs was found 6, 14, and 24-28 months after initiation. At the end of SAM treatment the number of PNs per rat liver, nodule diameter, and labeling and mitotic indices of nodular cells decreased considerably in control rats. Nodule diameter started to increase rapidly again only 8 months after arresting SAM treatment, when complete recovery of DNA synthesis in nodular cells occurred. The majority of nodules present in the liver 6-28 months after initiation belonged to the clear and acidophilic cell types, with lower percentages of mixed cell and basophilic cell types. A decrease in basophilic nodules occurred in SAM-treated rats. Fourteen and 24-28 months after initiation hepatocellular carcinoma incidence was 11 of 12 and 10 of 10 in control rats, respectively, and only 1 of 12 and 3 of 11 in SAM-treated rats. At the 24th-28th month all control rats had tumors identified as 2 poorly differentiated carcinomas, 6 trabecular carcinomas, or 3 adenocarcinomas, while only 2 relatively small trabecular carcinomas and 1 small glandular tumor developed in SAM-treated rats. In 3 of 11 SAM-treated rats, but in none of the control rats, leukemic infiltration of liver occurred 24-28 months after initiation. Leukemic infiltration of the spleen occurred in 5 and 3 control and SAM-treated rats, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Reversal by 5-azacytidine of the S-adenosyl-L-methionine-induced inhibition of the development of putative preneoplastic foci in rat liver carcinogenesis.

The development of gamma-glutamyltranspeptidase (GGT)-positive foci, in Wistar rats, initiated with diethylnitrosamine and subjected to selection according to 'resistant hepatocyte' protocol, was coupled, 7 weeks after initiation, with liver DNA hypomethylation and with a fall in S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio, and in 5-methylthio-adenosine (MTA) content. A 15-day treatment with SAM, started 1 week after selection, caused a dose-dependent decrease in the development of GGT-positive foci, recovery of liver SAM/SAH ratio and MTA level, and liver DNA methylation. A 12-day treatment with 20 mumol/kg per day of 5-azacytidine (AzaC), starting 1 week after selection, enhanced growth of GGT-positive foci, caused strong DNA hypomethylation, and partially counteracted the inhibition of GGT-positive foci growth, without affecting recovery of SAM/SAH ratio and MTA level, induced by SAM. These results suggest a role of DNA methylation in the antipromoting effect of SAM.

Adenosine↗
PubMed1991

Differential effects of dehydroepiandrosterone and deoxyribonucleosides on DNA synthesis and de novo cholesterogenesis in hepatocarcinogenesis in rats.

Previous studies from our laboratory have shown that dehydroepiandrosterone (DHEA), an inhibitor of glucose-6-phosphate dehydrogenase (G6PD), prevents the development of gamma-glutamyltranspeptidase (GGT)-positive foci in the early stages of hepatocarcinogenesis in rats. Since high rates of DNA and cholesterol (CH) synthesis are observed during promotion of carcinogenesis, and mevalonate (MVA), or some other intermediates of CH synthesis, could be mediators of DNA synthesis, we investigated the effect of DHEA on CH synthesis in rat liver during the development of GGT-positive foci. Hepatocarcinogenesis was induced by diethylnitrosamine in female Wistar rats by the Solt-Farber protocol (initiation/selection) with and without phenobarbital treatment. A 15 day treatment with DHEA (0.6% in the diet), started after selection, caused a great fall in labeling and mitotic indices of GGT-positive foci, which was prevented by the simultaneous administration of a mixture of four deoxyribonucleosides (DRNs) of adenine, guanine, cytosine and thymine or four ribonucleosides (RNs) of adenine, guanine, cytosine and uridine, but not by the corresponding bases. DHEA greatly inhibited G6PD activity and the production of ribulose-5-phosphate, without affecting NADPH levels, due to the compensatory increase in malic enzyme and isocitric dehydrogenase activities. Serum lecithin/cholesterol acyltransferase activity underwent a reduction in conditions allowing a rapid growth of GGT-positive tissue (absence of DHEA or presence of DHEA plus DRNs or RNs). Liver slices isolated from DHEA-treated rats showed a rise in CH content, coupled with a 80% fall in the incorporation of labeled acetate, but not of labeled MVA, into CH. A 25 day treatment of rats subjected to initiation/selection, started after the appearance of persistent nodules, caused a 36 and 78% fall in the incorporation, in vivo, of 3H2O into nodular and surrounding liver CH respectively. DRN did not counteract DHEA-induced inhibition on CH synthesis. Thus DHEA inhibits the CH biosynthetic pathway before MVA synthesis, in conditions (presence of DHEA plus DRN/RN) allowing rapid growth of preneoplastic lesions. Therefore, the development of these lesions does not need the synthesis of large amounts of CH and CH metabolites. Thus, the antipromotion effect of DHEA may depend on a decreased availability of pentose phosphates for DNA synthesis.

Animals↗
PubMed1990

Dependence of benzo(a)pyrene metabolism on NADPH pool in normal and glucose-6-phosphate dehydrogenase deficient human fibroblasts.

Human skin fibroblasts (HSF), from normal donors and donors carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase, grown in vitro in the presence of 0.25-5 microM benzo(a)pyrene (BaP), produced the following organic-soluble metabolites: 9,10-diol, 7,8-diol, quinones, 3- and 9-hydroxide and a more polar fraction, and the following water-soluble metabolites: more polar, 3- and 9-hydroxide and 9,10-diol. Single organic- and water-soluble metabolites increased with BaP concentration in both types of HSF, but the ratio normal/variant increased with BaP concentration. NADPH level and NADPH/NADP+ ratio underwent a slight decrease in normal HSF incubated with 2.5 microM BaP, while a greater fall occurred in the deficient HSF at 0.25 and 2.5 microM BaP. NADPH content seems to be rate-limiting for BaP metabolism in the deficient cells.

Adult↗
PubMed1989

Inhibition of promotion and persistent nodule growth by S-adenosyl-L-methionine in rat liver carcinogenesis: role of remodeling and apoptosis.

The resistant hepatocyte model (initiation/selection) and the triphasic model (initiation/selection followed by phenobarbital, for a maximum of 16 weeks) were compared for their ability to generate enzyme-altered foci (EAF) and nodules in the liver of Wistar rats initiated by diethylnitrosamine. The effects of S-adenosyl-L-methionine (SAM) on the development of preneoplastic tissue was tested in these experimental models. In the absence of phenobarbital (PB), EAF and early nodules (EN) went through a phase of rapid growth, between 4 and 9 weeks after initiation, to a phase in which progressive decrease in number and size occurred. By the 26th week only a few remodeling EAF and nodules were found. In PB-treated rats a rapid increase in the percentage of liver occupied by EAF and EN, up to the 9th week after initiation, was followed by a period of slow growth (from the 9th to the 20th week) and then, after PB withdrawal (20th week), by a drop in the number and size of EAF and EN. However, at the 26th week actively growing nodules with a low tendency to spontaneous remodeling (persistent nodules) developed. EAF and EN showed a high DNA synthesis 5 weeks after initiation. Thereafter, progressive decline in DNA synthesis, coupled with remodeling and decrease in number of biochemical markers, was seen both in the absence and, even though to a lesser extent, in the presence of PB, indicating that preneoplastic lesions became increasingly insensitive to PB. Relatively few apoptotic bodies could be observed in EAF and EN during PB treatment. After PB withdrawal, decrease in growth potential was coupled with increase in apoptotic bodies. In contrast, in persistent nodules relatively high apoptosis occurred which partially counterbalanced high DNA synthesis. Administration of SAM for a maximum of 16 weeks, starting at the 4th week after initiation, caused a great decrease in number and size of EAF and EN, associated with inhibition of DNA synthesis, high cell death by apoptosis, high remodeling, and loss of biochemical markers, in preneoplastic lesions of both PB-treated and untreated rats. A 1-8-week SAM treatment, started after the development of persistent nodules, caused a great regression of nodular lesions, coupled with a sharp fall in DNA synthesis and increase in apoptosis. It is suggested that inhibition by SAM of the development of preneoplastic tissue is linked to a shift of the equilibrium between cell production and cell death in favor of cell death.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1989

Inhibition by ethanol of rat liver plasma membrane (Na+,K+)ATPase: protective effect of S-adenosyl-L-methionine, L-methionine, and N-acetylcysteine.

(Na+,K+)ATPase activity of rat liver plasma membranes was evaluated in female rats feeding an ethanol containing diet for 46 days (total ethanol ingested, 59.7 g/100 g body wt). Determinations were performed at the end of ethanol treatment or at various times after stopping treatment. (Na+,K+)ATPase and 5'-nucleotidase activities exhibited a 8- and 1.4-fold decrease, respectively, at the end of ethanol ingestion. In contrast no modifications of Mg2+-ATPase activity were observed. There also occurred, in ethanol-treated rats, release of sorbitol dehydrogenase into the blood, fat accumulation in liver cells, and decrease in reduced glutathione (GSH) liver content. A decrease in (Na+,K+)ATPase activity was also found in plasma membranes isolated from hepatocyte suspensions after a 2-hr incubation with 50 mM ethanol or 1 mM acetaldehyde (ACA), in conditions that caused a great fall in hepatocyte GSH content but did not cause cell death. After the cessation of ethanol administration, there occurred a progressive recovery of (Na+,K+)ATPase activity, GSH and triacylglycerol content, and release of sorbitol dehydrogenase. These parameters reached control values 12 hr after ethanol withdrawal. S-Adenosyl-L-methionine (SAM), L-methionine, and N-acetylcysteine (NAC), given to rats during ethanol treatment, prevented the decrease in (Na+,K+)ATPase activity and GSH content. They also reduced steatosis and liver necrosis. The efficiency of these compounds decreased in this order: SAM, methionine, NAC. SAM accelerated the recovery of all parameters studied after ethanol withdrawal, and also protected (Na+,K+)ATPase activity and GSH content of isolated hepatocytes from the deleterious effect of ethanol. These SAM effects were prevented by 1-chloro-2,4-dinitro-benzene, a compound which depletes cell GSH. Treatment of isolated hepatocytes with [35S]SAM led to the synthesis of labeled GSH. The total amount and specific activity of labeled GSH underwent a significant increase, in the presence of 2 mM ethanol or 0.5 mM ACA, which indicates a marked stimulation of GSH synthesis by ethanol and ACA. These data indicate that ethanol intoxication may inhibit (Na+,K+)ATPase activity; an effect that does not seem to depend on cell necrosis. SAM, methionine, and NAC exert various degrees of protection toward ethanol-induced cell injury, which are related to the efficiency of these compounds in maintaining a high GSH pool.

Acetaldehyde↗
PubMed1989

Protooncogene methylation and expression in regenerating liver and preneoplastic liver nodules induced in the rat by diethylnitrosamine: effect of variations of S-adenosylmethionine:S-adenosylhomocysteine ratio.

S-adenosylmethionine:S-adenosylhomocysteine (SAM/SAH) ratio, 5-methylcytosine (5mC) DNA content, and methylation and expression of c-myc, c-Ha-ras and c-Ki-ras have been studied in liver nodules, induced by diethylnitrosamine according to the 'resistant hepatocyte' model, and in regenerating liver (RL) between 0.5 and 72 h after partial hepatectomy (PH). Nodules, 11, 13 and 21 weeks after initiation, grew actively, showed a low tendency to remodel (persistent nodules), and did not exhibit carcinomatous changes. They underwent extensive remodeling after a 1-week SAM treatment (64 mumol/kg/day), and decreased in size and number after a 3-11-week treatment. A low SAM/SAH ratio was coupled, in nodules, with a high labeling index (LI), 2-fold fall in 5mC DNA content, increase in c-myc, c-Ha-ras and c-Ki-ras expression and hypomethylation of CCGG sequences in the DNA hybridizing with the three protooncogenes. In RL a low SAM/SAH ratio, overall DNA hypomethylation and enhanced c-myc expression were first observed 0.5 h after PH, reached a peak at 5 h and progressively returned to pre-PH levels later on. Maximum expression of c-Ha-ras and c-Ki-ras occurred 24-30 h after PH, roughly coincident with the LI peak. However, no great modifications of the methylation pattern of protooncogene CCGG sequence occurred at any time after PH, indicating the presence of hypomethylated genes and/or DNA sequences different from those investigated in this paper. SAM injection to nodule-bearing rats, for 1-11 weeks before killing, and to hepatectomized rats, 2 days before PH and then up to killing, largely prevented decrease in the SAM/SAH ratio and overall DNA methylation and inhibited LI and protooncogene expression. In nodules these effects were proportional to the treatment length and coupled with methylation of CpG residues in the CCGG sequence of the three protooncogenes studied. SAM treatment left the methylation pattern of these genes unchanged in RL. Kinetics of increase in protooncogene expression suggest a role in the regulation of cell cycle in RL. However, decrease in the SAM/SAH ratio, protooncogene hypomethylation and enhanced expression are apparently stable in nodules 11-21 weeks after initiation and could be implicated in continuous nodule growth and progression. Control of DNA methylation and gene expression by exogenous SAM could be a mechanism of the SAM anti-progression effect.

Animals↗
PubMed1987

Benzo(a)pyrene metabolism by lymphocytes from normal individuals and individuals carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase.

In vitro growing human lymphocytes (HL) and fibroblasts, isolated from glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects (Mediterranean variant), show a sharp decrease in this enzymatic activity and in NADPH:NADP+ ratio. These cells are less able than controls to hydroxylate benzo(a)pyrene (BaP) when tested in the absence of an exogenous NADPH-generating system. They exhibit great resistance to the toxic effect of BaP. G6PD-deficient fibroblasts are less prone than controls to in vitro transformation by BaP. To investigate whether this depends on a decreased production of active BaP metabolites and BaP:DNA adducts by G6PD-deficient cells, BaP metabolism was studied in G6PD-deficient HL cultured in vitro in the presence of mitogens and treated with BaP for 24 hr. HPLC profiles of organo- and water-soluble metabolites revealed that both types of benzo(a)anthracene (BaA)-induced HL produced: 4,5-, 7,8-, 9,10-diols, 1,3-, 3,6-quinones, 3-, 9-hydroxy and 2 peaks of more polar metabolites. There was a 25-76% decrease of organo- and water-soluble metabolites in the G6PD-deficient cells. When HL were incubated with 7,8-diol, the formation of metabolites mutagenic for Salmonella typhimurium (His-) was very low in G6PD-deficient cells. BaP:deoxyadenosine (dAde) and BaP:deoxyguanosine (dGua) adducts were identified after incubation of both types of HL with BaP. There was a 31-79% fall in adduct formation by G6PD-deficient cells. Our results indicate that G6PD-deficient human lymphocytes are less able to metabolize BaP than normal lymphocytes. We suggest that the NADPH pool is inadequate, in deficient cells, for active BaP metabolism.

Benzo(a)pyrene↗
PubMed1987

Decreased stimulation by 12-O-tetradecanoylphorbol-13-acetate of superoxide radical production by polymorphonuclear leukocytes carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase.

Polymorphonuclear leukocytes (PMNs) from individuals carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase (G6PD) exhibit a great decrease in this enzymatic activity and in hexose monophosphate shunt (HMS). 12-O-tetradecanoylphorbol-13-acetate (TPA) greatly stimulates HMS of normal PMNs, while it does not affect that of the deficient PMNs. Similarly, the stimulation of HMS by methylene blue is largely reduced in G6PD-deficient PMNs. These changes are paralleled by a 58% decrease in TPA-stimulated superoxide radical (O2-) formation by the deficient PMNs. G6PD activity is not detectable in the deficient PMNs incubated with dehydroepiandrosterone, and these cells show a near complete inhibition of O2- production. It thus seems that the low ability of G6PD-deficient PMNs in the production of O2- depends on the low NADPH generation by HMS in these cells. The decrease in TPA-stimulated O2- production suggests a reduced response of G6PD-deficient cells to promoting agents.

Adult↗
PubMed1987

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.

Liver ornithine decarboxylase (ODC) activity and content of S-adenosyl-L-methionine (SAM) and its catabolite 5'-methylthioadenosine (5'-MTA) were determined in the late stages of hepatocarcinogenesis. Wistar rats received one diethylnitrosamine dose, followed by a partial hepatectomy at the midpoint of a 15-day treatment with 2-acetylaminofluorene (2-AAF), and then by an 18-week phenobarbital (PB) treatment. Thirty-eight per cent of liver was gamma-glutamyltranspeptidase (GGT)-positive and no visible nodules and hepatocellular carcinomas developed 16 weeks after starting 2-AAF feeding. Hyperplastic nodules and hepatocellular carcinomas were found on weeks 24 and 56 respectively. On weeks 24 and 56 only approximately 10% of liver was occupied by GGT-positive foci. At all times studied the foci exhibited a low labeling index (LI), and liver ODC activity was near control values. By contrast, a high ODC activity and LI and a low SAM and 5'-MTA levels were found in hyperplastic nodules and neoplasia. These tissues exhibited a high 5'-MTA phosphorylase activity. SAM administration during PB treatment, caused a 25-36% fall of GGT-positive liver and prevented the development of hyperplastic nodules and hepatocellular carcinomas. This was coupled to a sharp increase of SAM and 5'-MTA liver contents. SAM and 5'-MTA inhibited hepatocyte DNA synthesis in vitro. The addition of 5'-MTA to the reaction mixture for the ODC assay strongly inhibited ODC activity. However, the preincubation of SAM with liver homogenates or hepatocytes, used to prepare crude ODC, was necessary to inhibit ODC activity by SAM. Adenine, an inhibitor of 5'-MTA-phosphorylase, enhanced inhibition of DNA synthesis and ODC activity by SAM and 5'-MTA. Thus, during a prolonged promoting treatment a selected population of GGT-positive foci appears to acquire a stable phenotype characterized by a high DNA and polyamine synthesis. The development of nodules and carcinomas is associated with low SAM and 5'-MTA contents and high ODC activity and LI. 5'-MTA accumulation, during SAM administration, is probably responsible for the inhibition of promotion by SAM.

2-Acetylaminofluorene↗
PubMed1987

The variations of S-adenosyl-L-methionine content modulate hepatocyte growth during phenobarbital promotion of diethylnitrosamine-induced rat liver carcinogenesis.

A decrease in liver S-adenosyl-L-methionine (SAM) content and an increase in ornithine decarboxylase (ODC) activity occurred between the 2nd and the 5th week after starting 2-acetylaminofluorene (AAF) feeding in diethylnitrosamine (DENA)-initiated rats. These rats then received a 0.05% phenobarbital (PB)-containing diet for 18 weeks after the end of AAF feeding. Two weeks after starting AAF, an increase in the hepatocyte labeling index (LI) also occurred in gamma-glutamyl-transpeptidase (GGT)-positive foci and surrounding tissue. LI returned to control values in a few days in surrounding tissue, while it remained high for at least 4 weeks in the foci. Analogous changes were observed, but for a shorter period of time, in the rats subjected to partial hepatectomy (PH) plus AAF, in which no GGT-positive foci developed. Twenty-four weeks after starting AAF, 30% of the liver was occupied by visible nodules. ODC activity and LI were high and SAM was low in nodules, but they were near to control values in surrounding liver. SAM administration reconstituted the liver SAM pool, inhibited ODC activity, and prevented visible nodule development. SAM inhibition of ODC activity occurred in vitro only after preincubation with liver homogenate and was enhanced by adenine, an inhibitor of methylthioadenosine (MTA) phosphorylase. MTA addition to the reaction of mixture for ODC determination was inhibitory. The SAM decrease in both liver and nodules was coupled with a decrease of MTA content. SAM administration caused MTA accumulation in the liver. It is suggested that liver SAM content by influencing MTA level, could be a rate-limiting factor for growth and promotion, through a modulation of polyamine synthesis.

2-Acetylaminofluorene↗
PubMed1987

Control of glucose-6-phosphate dehydrogenase deficiency on the formation of mutagenic and carcinogenic metabolites derived from benzo(a)pyrene.

It has been observed that human lymphocytes (HL) and fibroblasts, isolated in vitro from donors carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase (G6PD), show a great decrease in this enzymatic activity, the hexose monophosphate shunt, and the NADPH/NADP+ ratio. This effect is associated with a decreased sensitivity of G6PD-deficient cells to the benzo(a)pyrene (BaP) cytotoxic effect and to a decreased in vitro transformation of BaP-treated fibroblasts. Further, benzo(a)anthracene (BaA)-induced BaP hydroxylase activity is lower in G6PD-deficient cells, when measured in the presence of endogenous NADPH. It has been hypothesized that the NADPH level could be rate-limiting for the NADPH-dependent steps of BaP metabolic activation. To test this hypothesis, the formation of BaP metabolites was studied in normal and G6PD-deficient HL incubated with the carcinogen. HPLC profiles of organic-soluble metabolites revealed that both types of HL produced all the following known BaP metabolites: 9,10-, 4,5- and 7,8-dihydrodiols, quinones, 9- and 3-hydroxy and two peaks of more polar metabolites. There was a great decrease of the various metabolites in the deficient HL. A decrease of total water-soluble BaP metabolites also occurred. HL formed mutagenic metabolites for S. typhimurium TA100 (his-) when incubated with the rat liver S9 fraction. When intact HL substituted S9 fraction, a significant reversed mutation occurred only with normal HL. This could indicate that the NADPH pool is inadequate in G6PD-deficient HL for active BaP metabolism. Accordingly, deficient HL formed lower amounts of BaP:DNA adducts than control during incubation with BaP.

Benzo(a)pyrene↗
PubMed1987

Inhibition by dehydroepiandrosterone of liver preneoplastic foci formation in rats after initiation-selection in experimental carcinogenesis.

The effect of dehydroepiandrosterone (DHEA) on the development of liver preneoplastic foci was evaluated. The experimental protocol used initiation by diethylnitrosamine (DENA), followed by selective growth induced by partial hepatectomy (PH), in rats fed an N-acetylamino-fluorene (AAF)-containing diet, and followed by a standard diet with or without 0.05% phenobarbital (PB). DHEA (0.6%) was administered in the diet for 4 or 7 weeks after DENA injection (treatments A and B) or for 3 weeks after the end of AAF feeding (treatment C). On the 7th week after DENA injection, DHEA treatments A and C caused slight decrease of body weight and 40-60% increase in liver weight and cell size; number of nuclei per g of liver was not changed. The dietary treatment also caused a marked decrease of liver glucose-6-phosphate dehydrogenase (G6PD) activity and of the percentage of the gamma-glutamyltranspeptidase (GGT)-positive liver. PB increased G6PD activity and GGT-positive liver. This effect was oblated by DHEA treatments A and C. On the 7th week, the labeling index (LI) was low in surrounding liver, and high in GGT-positive foci. PB had an enhancing effect, while DHEA treatments A and C were inhibitory. G6PD was low at the end of DHEA treatment B, but it returned to normal values 4 weeks after the end of this treatment. At this time no effect of DHEA treatment B was observed on the extent of GGT-positive liver and LI.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Acetylaminofluorene↗
PubMed1986

Effect of the variations of S-adenosyl-L-methionine liver content on fat accumulation and ethanol metabolism in ethanol-intoxicated rats.

The protective effect of S-adenosyl-L-methionine against rat liver steatosis induced by chronic ethanol ingestion was investigated. S-Adenosyl-L-methionine given during ethanol treatment prevented steatosis and accelerated recovery from steatosis when given after ethanol withdrawal. It also caused a slight inhibition of blood ethanol consumption in both acutely and chronically intoxicated rats. About 30% inhibition of alcohol dehydrogenase, but not of the microsomal ethanol oxidation system, occurred in rats subjected to acute ethanol toxicity as well as in normal rats as a consequence of S-adenosyl-L-methionine treatment. A comparison between S-adenosyl-L-methionine and pyrazole, as concerns inhibition of ethanol oxidation and fat accumulation, revealed that a greater inhibition of ethanol metabolism by pyrazole was associated with incomplete prevention of steatosis, while a lower inhibition by S-adenosyl-L-methionine was coupled to a complete prevention. Ethanol induced a drastic decrease of reduced glutathione liver content as well as 630 and 133% increases of blood and liver acetaldehyde contents, respectively. S-Adenosyl-L-methionine treatment almost completely reconstituted the liver reduced glutathione pool and caused a large decrease of the liver and blood acetaldehyde contents. 1-Chloro-2,4-dinitrobenzene, which depletes the cellular reduced glutathione, and diethylethanolamine, an inhibitor of the phosphatidylethanolamine methylation, abolished the S-adenosyl-L-methionine-induced modifications of the reduced glutathione, acetaldehyde, and triacylglycerol contents in the liver of ethanol-treated rats. Neither S-adenosyl-L-methionine nor reduced glutathione inhibitors affected the liver acetaldehyde dehydrogenase activity. It is suggested that, although S-adenosyl-L-methionine induced a small inhibition of ethanol metabolism in the liver, its antisteatosic effect could largely depend on its role as a modulator of the reduced glutathione liver content.

Acetaldehyde↗
PubMed1985

Early stimulation of polyamine biosynthesis during promotion by phenobarbital of diethylnitrosamine-induced rat liver carcinogenesis. The effects of variations of the S-adenosyl-L-methionine cellular pool.

A decrease of S-adenosyl-L-methionine liver content was observed between the 14th and the 35th day after the start of 2-acetylaminofluorene feeding in diethylnitrosamine-initiated rats according to the 'resistant-hepatocyte' model of hepatocarcinogenesis. The decrease was enhanced by phenobarbital given to the animals after the end of 2-acetylaminofluorene feeding. These changes were associated with an increase in ornithine decarboxylase activity and the spermidine:spermine ratio. S-adenosyl-L-methionine administration to rats caused a great fall in the percentage of gamma-glutamyltranspeptidase-positive liver as well as in polyamine synthesis. An increase in ornithine decarboxylase activity, associated with a decrease in the liver S-adenosyl-L-methionine pool, also occurred in normal animals on the first day following a partial hepatectomy and was enhanced by phenobarbital. The association of 2-acetylaminofluorene feeding with partial hepatectomy resulted in a slower liver regeneration, while the decrease in S-adenosyl-L-methionine level and the increase in polyamine synthesis were observed over a longer period of time after partial hepatectomy. These changes were further prolonged in diethylnitrosamine-initiated rats in which gamma-glutamyltranspeptidase-positive foci developed. In these animals a high level of polyamine synthesis was still present when liver regeneration was complete. At this stage of the observation period the labeling index was very low in surrounding liver, but still high in the gamma-glutamyltranspeptidase-positive areas. Phenobarbital stimulated polyamine synthesis and cell growth and further prolonged the period of time during which a high ornithine decarboxylase activity and labeling index were present. These results indicate that the liver lipotrope content could be a rate-limiting factor for cell growth and liver neoplasia promotion and this could depend on the modulation of polyamine biosynthesis.

2-Acetylaminofluorene↗