Hepatic Ornithine Decarboxylase Activity Research Articles

Metabolic and immune effects of orange-spotted grouper, Epinephelus coioides induced by dietary arginine

Arginine (Arg) as an important substrate for protein metabolism and endocrine influences on fish health directly. To evaluate the effect of dietary Arg on these endocrine and immunity of juvenile orange-spotted grouper (Epinephelus coioides), an experiment adding Arg with 0.00, 0.30, 0.60, 0.90, 1.20, 1.50, and 1.80% in seven diets was conducted. Dietary Arg levels reached 2.13 (Diet 1), 2.42 (Diet 2), 2.71 (Diet 3), 2.95 (Diet 4), 3.20 (Diet 5), 3.48 (Diet 6) and 3.74% (Diet 7), respectively. Each treatment was randomly assigned to triplicate groups of 30 fish (7.52 ± 0.02 g) each tank. The present results indicated that different Arg levels of diets were no significant effects on the fish survival rate of each groups (P > 0.05) after 8 weeks feeding experiment. The highest weight gain and specific growth rate were found in Diet 4, and significantly higher than the other groups (P < 0.05). Hepatic arginase activities were significantly higher in fish fed Diet 6 and Diet 7 compared to the activities of the fish fed first three Diets (P < 0.05). Hepatic ornithine decarboxylase activities of fish fed Diet 1 and Diet 2 were significantly decreased compared to the fish fed Diet 4–Diet 7 (P < 0.05). With ascending dietary Arg, the serum Insulin (INS) and insulin-like growth factor I (IGF-I) levels significantly increased. Gene expression of tissue toll-like receptors 22 in the three tissues were found first up-regulated and then down-regulated with the Arg increasing. Gene expression of major histocompatibility complex II in liver and kidney significantly increased in fish fed Diet 4 and Diet 6, and decreased thereafter. However, gene expression of hepcidin decreased with dietary Arg increased. The present study showed alterations in serum INS and IGF-I levels in response to Arg-induced growth activation. Additionally, the results indicate that Arg has beneficial effects on regulating mRNA expression of immune-associated genes and improving humoral and cellular immunity of fish.

The Increase in Liver Polyamine Concentration Contributes to the Tryptophan‐induced Stimulation of Hepatic Protein Synthesis

Tryptophan has a unique role as a nutritional signaling molecule that regulates protein synthesis in mice and rat liver. However, the mechanism of the stimulating actions of tryptophan on hepatic protein synthesis has not been clearly elucidated. Tryptophan has been suggested to stimulate protein synthesis at the translational level, because polysome aggregation was observed in a short time after oral administration of tryptophan. Therefore, we focused on the acute effects of tryptophan on protein synthesis. In the present study, proteomic and metabolomic analysis was performed to identify candidate proteins and metabolites, which are likely to play a role in stimulation of protein synthesis by tryptophan. Eighteen hours fasted Wistar rats were divided into 3 groups. One group of animals was sacrificed without any treatment as a control. Remaining two groups of animals were administered 135mg/100g body weight L‐tryptophan by oral gavage and then sacrificed after 1h or 3h after administration. With two‐dimensional electrophoresis and image analysis, four differentially expressed protein spots were detected at 3h after administration of tryptophan, and one of which was identified as key enzyme in the biosynthetic pathway of ornithine, ornithine aminotransferase (OAT) precursor. OAT is the main catabolic enzyme of ornithine and its expression was significantly decreased by tryptophan administration. The concentration of ornithine was increased in both serum and liver at 3h after administration of tryptophan. Ornithine is a precursor for polyamine biosynthesis. Ornithine decarboxylase (ODC) catalyzes the first step in the polyamine biosynthetic pathway forming putrescine, which is then converted into the polyamines spermidine and spermine. It has been reported that oral administration of tryptophan to overnight‐fasted rats exhibited increase in the hepatic ODC activity. Significantly increased concentrations of polyamines, as well as ornithine were found in the liver at 3h after administration of tryptophan. Based on these results, we speculate that the increase in ornithine level through suppression of OAT expression and stimulation of ODC activity by tryptophan administration may lead to accelerated polyamine synthesis and thereby promote protein synthesis in the liver.

Emblica officinalis reverses thioacetamide-induced oxidative stress and early promotional events of primary hepatocarcinogenesis

Emblica officinalis is widely used in Indian medicine for the treatment of various diseases. In the present study, it was found that fruits of E. officinalis inhibit thioacetamide-induced oxidative stress and hyper-proliferation in rat liver. The administration of a single necrotic dose of thioacetamide(6.6 mM kg(-1)) resulted in a significant (P < 0.001) increase in serum glutamic oxaloacetic transaminase(SGOT), serum glutamic pyruvic transaminase (SGPT) and gamma-glutamyl transpeptidase (GGT) levels compared with saline-treated control values. Thioacetamide caused hepatic glutathione (GSH) depletion and a concomitant increase in malanodialdehyde (MDA) content. It also resulted in an increase(P < 0.001) in the activity of glutathione-S-transferase (GST), glutathione reductase (GR), glucose 6-phosphate dehydrogenase (G6PD) and a decrease in glutathione peroxidase (GPx) activity (P < 0.001). Hepatic ornithine decarboxylase activity and thymidine incorporation in DNA were increased bythioacetamide administration. Prophylactic treatment with E. officinalis for 7 consecutive days before thioacetamide administration inhibited SGOT, SGPT and GGT release in serum compared with treated control values. It also modulated the hepatic GSH content and MDA formation. The plant extract caused a marked reduction in levels of GSH content and simultaneous inhibition of MDA formation. E. officinalis also caused a reduction in the activity of GST, GR and G6PD. GPx activity was increased after treatment with the plant extract at doses of 100 mg kg(-1) and 200 mg kg(-1). Prophylactic treatment with the plant caused a significant down-regulation of ornithine decarboxylase activity (P < 0.001) and profound inhibition in the rate of DNA synthesis (P < 0.001). In conclusion, the acute effects of thioacetamide in rat liver can be prevented by pre-treatment with E. officinalis extract.

Protective Effects of Picorrhiza Kurroa Extract against 2-Acetylaminofluorene-Induced Hepatotoxicity in Wistar Rats

Picrorrhiza kurroa has been shown to impart significant hepatoprotective activities, partly by modulation of free radical--induced lipid peroxidation. Lipid peroxidation and reactive oxygen species are associated with hepatic injury. The effect of P. kurroa treatment on the antiproliferative response and, hepatic antioxidant enzymes of rats administered with 2-acetylaminofluorene (2-AAF) was studied in Wistar rats. 2-AAF (50 mg/kg body weight, i.p.) enhances hepatic lipid peroxidation, with reduction in hepatic glutathione content, glutathione peroxidase, glutathione reductase, catalase, and glutathione-s-transferase. There was an increase in the levels of transaminase enzymes and LDH. 2-AAF treatment also enhanced ornithine decarboxylase (ODC) activity and [3H] thymidine incorporation into hepatic DNA. Pretreatment of rats orally with P. kurroa extract (250 and 500 mg/kg body weight) resulted in significant decrease in lipid peroxidation, transaminase enzymes, LDH, hepatic ODC activity, and DNA synthesis (p < 0.001). Hepatic glutathione content (p < 0.001), glutathione metabolizing enzymes (p < 0.001), and antioxidant enzymes were also recovered to significant level (p < 0.001).

Abrogation of Thioacetamide-Induced Biochemical Events of Hepatic Tumor Promotion Stage by Tannic Acid in Wistar Rats

Tannic acid is present in almost every edible plant and is generally used as a safe food additive. In this study we investigated the antioxidative and antihyperproliferative potential of tannic acid against thioacetoamide (TAA), a potent hepatotoxic-substance-induced oxidative stress and hyperproliferation biomarker. We have shown here that the activities of hepatic antioxidant enzymes, phase II metabolizing enzymes, and the glutathione content were decreased while hepatic ornithine decarboxylase activity and DNA synthesis were induced in TAA-treated animals. Tannic acid administration at two different doses prior to the TAA injection partially recovered the depleted level of glutathione, inhibited activities of antioxidant and phase II metabolizing enzymes, and resulted in significant inhibition of oxidative stress in a dose-dependent manner. Tannic acid administration before TAA treatment also resulted in a significant decrease in ODC activity and [3H]-thymidine incorporation in rat liver, which are classical markers of inflammation and tumor promotion. Our data clearly demonstrate that tannic acid possesses antioxidant and antiproliferating activities because it inhibits early biomarkers of TAA-induced tumor promotion in an in vivo animal model.

Vitamin E inhibits hepatic oxidative stress, toxicity and hyperproliferation in rats treated with the renal carcinogen ferric nitrilotriacetate

Ferric nitrilotriacetate (Fe-NTA) is a potent renal and hepatic tumor promoter, which acts through a mechanism involving oxidative stress. Fe-NTA when injected intraperitoneally into rats induces hepatic ornithine decarboxylase activity as well as hepatic DNA synthesis. Vitamin E is a well-known, lipid-soluble and chain-breaking antioxidant which protects cell membranes from peroxidative damage. In this study, we investigated the protective effect of vitamin E, a major fat-soluble antioxidant, against Fe-NTA-mediated hepatic oxidative stress, toxicity and hyperproliferation in Wistar rats. Animals were treated with two different doses of vitamin E for 1 week prior to Fe-NTA treatment. Vitamin E at a higher dose of 2.0 mg/animal/day showed significant reduction in Fe-NTA-induced hepatic ornithine decarboxylase activity, DNA synthesis, microsomal lipid peroxidation and hydrogen peroxide generation. Fe-NTA treatment alone caused depletion of glutathione, glutathione metabolizing and antioxidant enzymes in rat liver, whereas pretreatment of animals with vitamin E reversed these changes in a dose-dependent manner. Taken together, our results suggest that vitamin E may afford substantial protection against the damage caused by Fe-NTA exposure and can serve as a potent preventive agent to suppress oxidant-induced tissue injury.

Inhibitory effect of celery seeds extract on chemically induced hepatocarcinogenesis: modulation of cell proliferation, metabolism and altered hepatic foci development

The chemopreventive activity of methanolic extract of Apium graveolens seeds (celery seeds) has been investigated against Solt Farber protocol of hepatocarcinogenesis, oxidative stress and induction of positive foci of γ-GT in the liver of Wistar rats. The prophylactic treatment of celery seeds extract protected dose dependently against diethylnitrosoamine (DEN)+2-acetylaminofluorine (AAF)+partial hepatectomy (PH) induced hepatocarcinogenesis and other related events such as induction of γ-GT positive foci ( P<0.001). 2-AAF administration in diet with PH in rats resulted in increased hepatic ornithine decarboxylase (ODC) activity and a consequent increase in the rate of DNA synthesis when compared to saline treated control group while pretreatment of rats with celery seeds extract resulted in inhibition of aforementioned parameters dose dependently. The augmentation of quinone reductase (QR), glutathione- S-transferase (GST) and serum γ-glutamyl transpeptidase (GGT) activities; and depletion of the tissue GSH content after 2-AAF (i.p. injection) for five consecutive days was prevented with the administration of celery seed extract. On the basis of the above results it can be said that A. graveolens is a potent plant against experimentally induced hepatocarcinogenesis in Wistar rats.

Liver development in a rat model of fetal alcohol syndrome.

The inhibitory effects of alcohol on hepatic growth in adults raises the possibility that the liver may be involved in fetal alcohol syndrome (FAS) in infants. To test this hypothesis, pregnant Sprague-Dawley rats were fed liquid diets containing either ethanol as 36% of the total calories, or were allowed ad libitum feeding of a control liquid diet (controls) throughout pregnancy. Other dams were exposed to the ethanol diet only during the first or last half of pregnancy. Pups delivered of dams exposed to the various diets (N = 40-45/group) were killed at 1, 3, 7, and 14 days of age. In addition to brain weights, crown-rump lengths, and facial features, the following parameters of liver development were documented; liver weight, liver/body weight ratio, liver histology, hepatic ornithine decarboxylase activity (ODC), hepatic protein content, and rate of hepatic DNA synthesis (as determined by [3H]thymidine incorporation). The results revealed that pups exposed to ethanol throughout pregnancy but not ad libitum control diet pups had brain weights, crown-rump lengths, and facial features in keeping with FAS. With respect to liver development, the livers in FAS pups were consistently smaller than in the control group. However, total body weights were decreased to a greater extent, such that when corrected for body weights, the smaller livers in FAS pups only became significant on day 14 of life. Liver histology was similar in the two groups with no signs of active inflammation or fibrosis. Hepatic ODC activity was also similar, indicating no impairment in polyamine synthesis. Hepatic DNA synthesis rates were decreased in FAS pups at all time intervals. Pups delivered of dams exposed to ethanol during either the first or last half of pregnancy had results comparable to those of controls. To identify the mechanism(s) responsible for these findings, a second series of experiments was performed wherein the hepatic expression of the following factors associated with liver development were documented by northern-blot analyses; growth hormone receptor (GHr), insulin-like growth factor-I (IGF-I) and -II (IGF-II) and IGF binding proteins (IGFBPs) 1, 2, 3, and 4 mRNA on gestational days 16 and 20 and postpartum days 1 and 7. In this series, a third group of pups derived from dams in whom caloric consumption was matched to that of the ethanol-fed dams (isocaloric controls) were also studied. The results revealed no consistent differences in GHr, IGF, or IGFBP mRNA expression in the three groups. In conclusion, liver development and hepatic DNA synthesis were significantly impaired in this animal model of FAS. That impairment, however, was not associated with decreases in either polyamine synthesis or disturbances in the hepatic component of the GH/IGF/IGFBP axis.

Enhancement of biliary excretion of aflatoxin B 1 and suppression of hepatic ornithine decarboxylase activity by 2-(allylthio)pyrazine in rats

2-(Allylthio)pyrazine (2-AP), a synthetic pyrazine derivative with an allylsulfur moiety, has protective effects against chemically-induced hepatic toxicity. Previous studies have shown that 2-AP significantly reduces the formation of preneoplastic foci in rats exposed to aflatoxin B 1 (AFB 1). The present study was designed to determine whether 2-AP could increase the biliary excretion of metabolites of AFB 1 in rats treated with this carcinogen and whether the agent could alter the activity of ornithine decarboxylase (ODC), which is considered to be associated with tumor promotion. Rats were pretreated with 2-AP (p.o.) at a daily dose of 50 mg/kg for 5 consecutive days. AFB 1 (5 mg/kg) was administered intraperitoneally 2 h after the last dose of 2-AP. Amounts of principal AFB 1 metabolites, AFB 1-glutathione and a glucuronide conjugate secreted in bile juice was increased by 56 and 50%, respectively, after the 2-AP treatment. Levels of radiolabelled AFB 1 covalently bound to calf thymus DNA catalyzed by microsomes obtained from 2-AP-treated rats (10 and 50 mg/kg, for 5 days) were reduced by 47 to 66%. ODC activity in AFB 1-treated rats was determined by the three-step medium-term hepatocarcinogenesis assay. Rats were treated with 2-AP at the daily doses of 10, 25 and 50 mg/kg for 16 consecutive days. During this period, four repeated doses of AFB 1 (1.0 mg/kg) were given to the animals. Rats were then subjected to two-third partial hepatectomy, followed by administration of phenobarbital. 2-AP inhibited AFB 1-induced ODC activity by 40 to 66%, as determined at the 44th day. Inhibition of AFB 1-induced ODC activity by 2-AP in conjunction with acceleration of AFB 1 elimination through metabolic conjugation may contribute to its chemopreventive effects against this carcinogen.

Copper-nitrilotriacetate (Cu-NTA) is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen.

Earlier we have shown that ferric-nitrilotriacetate (Fe-NTA) is a hepatic as well as renal tumor promoter and acts by elaborating oxidative stress. In this study we show that copper-nitrilotriacetate (Cu-NTA) is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen. Similar to Fe-NTA, Cu-NTA has an ability to induce hepatic ornithine decarboxylase (ODC) activity dose-dependently. The maximum induction in hepatic ODC activity was observed 12 h after Cu-NTA treatment. However, renal ODC activity showed no significant changes at any time point and dose regimen studied. Similarly, hepatic and renal DNA synthesis which are measured as [3H]thymidine incorporation were increased dose-dependently in both the organs after Cu-NTA treatment. Unlike Fe-NTA, Cu-NTA administration had no significant effect on hepatic and renal glutathione, and on the activities of glutathione reductase, glutathione-S-transferase and catalase. In liver, saline-alone, DEN-alone, Cu-NTA-alone or DEN + Cu-NTA treated animals showed no hepatic tumors. Liver histology from only DEN-initiated and saline-treated control animals showed occasional appearance of a typical cell with large nucleus. Treatment of Cu-NTA to uninitiated and initiated animals showed more or less similar hepatic histology. Treatment of Cu-NTA to DEN-initiated animals resulted in the proliferative changes characterized by extensive hepatocellular hyperplasia. In case of kidney, the treatment of Cu-NTA to both the DEN-initiated and uninitiated animals led to the development of renal cell tumors. Treatment of Cu-NTA to the uninitiated animals produced renal cell tumors in about 18.7% animals. However, treatment of Cu-NTA to the DEN-initiated animals led to the development of renal cell tumors in 77.7% animals, of which most of the tumors were bilateral. However, DEN-initiated and saline-treated control animals showed no evidence of tumors. Our data indicate that Cu-NTA is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen.

Effect of liver hydrolysate on hepatic proliferation in regenerating rat liver

The effect of liver hydrolysate (LH) derived from bovine liver on rat liver regeneration after partial hepatectomy (PH) were investigated. Oral administration of LH increased rat liver weight dose-dependently at 24 h after PH. Hepatic ornithine decarboxylase (ODC) activity and proliferating cell nuclear antigen (PCNA) labeling index were measured in regenerating rat liver as markers of cell proliferation. ODC activities at 4 and 24 h after PH were significantly increased by LH administration. PCNA labeling index at 24 h after PH were also increased by LH administration. These results suggest that LH stimulates liver regeneration in partially hepatectomized rats.

Relationship between glutathione and polyamine metabolism after partial hepatectomy in alcohol-treated rats.

In a liver regeneration inhibiting model after partial hepatectomy in rats, we determined hepatic glutathione concentration and studied its relation with polyamine, an indicator of liver regeneration. Experiment 1: Male ODS rats and Wistar rats as control were maintained with vitamin C-deficient diets for 2 weeks. In the alcohol group, 3 g/kg of ethanol was administered orally 1 hr before partial hepatectomy. Experiment 2: Wistar rats were divided into four groups, according to the presence or absence of alcohol and vitamin E (VE), and a 6-week pair-feeding was done. As for partial hepatectomy, about 70% of the total liver was excised. As a result, in experiment 1, hepatic glutathione levels were significantly decreased by acute alcohol administration in both ODS and Wistar rats, and its level of alcohol administration group of ODS rats was the lowest. Hepatic ornithine decarboxylase activity and putrescine level 4 hr after partial hepatectomy showed almost a similar behavior, being the lowest in the alcohol administration group of ODS rats. In experiment 2, hepatic glutathione level showed no influence by chronic alcohol administration, but was the lowest in the VE-deficient alcohol administration group. Hepatic ODC activity and putrescine level 4 hr after partial hepatectomy showed no influence by chronic alcohol administration, but was the lowest in the VE-deficient alcohol administration group. These results clarified that intrahepatic glutathione levels before partial hepatectomy were decreased in the models in which hepatic ODC activities after surgery were suppressed.

Effects of eicosanoids on lipopolysaccharide-induced ornithine decarboxylase activity and polyamine metabolism in the mouse liver

Background/Aims: During endotoxic shock, arachidonic acid is released from the inflammatory cell membranes and is metabolized to form eicosanoids, which modify the deleterious effects of lipopolysaccharide (LPS) on liver function, However, it is not known which protaglandins (PGs) or leukotrienes (LTs) are produced or how they affect the LPS-treated liver. As LPS treatment elevates hepatic ornithine decarboxylase (ODC) activity and affects the polyamine levels of the mouse liver, this study was carried out to examine the effects of eicosanoids and their inhibitors on the induction of ODC activity and polyamine levels in the LPS-treated mouse liver.Methods: LPS in the presence or absence of other drugs was intraperitoneally administered to 6-week-old mice and the livers were then removed. The hepatic ODC activity, polyamine levels, and level of ODC mRNA were determined.Results: The levels of LPS-induced ODC activity, the putrescine (PUT) and N1-acetylspermidine (A-SPD) were reduced by the administration of PGE1. ODC activity was enhanced by the administration of corticosteron, AA-2414 (an antagonist of thromboxane (TX) A2) and TXB2, whereas the A-SPD level was reduced by corticosterone and AA-2414 treatment. The level of ODC mRNA changed in parallel with the change in OdC activity.Conclusions: PGE1 may reduce the LPS-induced production of inflammation-accelerating cytokines and reduce the level of ODC activation. Corticosterone and AA-2414 treatment may attenuate the LPS-induced production of eicosanoids, and enhance the LPS-induced ODC activation. It is possible that the eicosanoids produced by LPS treatment inhibit ODC activation during endotoxic shock.

Central administration of morphine inhibits brain and liver ornithine decarboxylase activity in neonatal rats: Involvement of transcription- and non-transcription-dependent mechanisms

This study examined whether the developmental deficits usually observed in infants born to opiate addicted mothers could involve effects on ornithine decarboxylase, a growth-controlling enzyme. Intracerebroventricular (i.c.v.) injection of a single dose of morphine (2 μg) to 6-day-old rats markedly decreased basal brain and liver ornithine decarboxylase activity as well as the increases in hepatic ornithine decarboxylase activity produced by subcutaneously (s.c.) administered insulin, an important trophic hormone. Centrally applied morphine acts supraspinally to downregulate peripheral ornithine decarboxylase activity, since s.c. administration of the same dose as used i.c.v. decreased neither basal liver ornithine decarboxylase levels nor tissue responsiveness to insulin. This does not imply that the opiate is unable to affect ornithine decarboxylase when applied systemically. In fact, a robust inhibition of both basal and induced liver ornithine decarboxylase activity was obtained in rat pups given 20 μg of morphine s.c. This larger dose is able to trigger the hepatic ornithine decarboxylase effects presumably by stimulating opiate receptors located at central sites after crossing the blood–brain barrier and penetrating into the brain. Concomitant administration of naloxone plus morphine i.c.v. prevented morphine from downregulating ornithine decarboxylase activity, confirming the participation of supraspinal opioid receptors in morphine ornithine decarboxylase actions. Finally, as was the case for insulin induced stimulation of ornithine decarboxylase activity, i.c.v. injection of morphine markedly diminished insulin induced stimulation of hepatic ornithine decarboxylase mRNA accumulation. In turn, contrary to the inhibition of basal ornithine decarboxylase activity, morphine did not lower basal hepatic ornithine decarboxylase mRNA levels when given alone. Thus, CNS morphine can apparently suppress tissue ornithine decarboxylase expression through both transcriptional and posttranscriptional mechanisms. The evidence obtained suggest that postnatal exposure to opiate drugs might detrimentally affect development by altering normal tissue ornithine decarboxylase ontogeny.

Dimethylarsinic acid treatment alters six different rat biochemical parameters: Relevance to arsenic carcinogenesis

In a previous study, we found that sodium arsenite increased hepatic ornithine decarboxylase (ODC) activity and hepatic heme oxygenase (HO) activity, but did not cause any DNA damage in adult female rat liver or lung, suggesting that arsenite may be a promoter of carcinogenesis. In this study sodium arsenate, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) were administered orally in equitoxic doses to adult female rats at 21 and 4 h prior to sacrifice. DNA damage (DD), cytochrome P450 content (P450), glutathione content (GSH), ODC, serum alanine aminotransferase (ALT) and HO were measured in liver and/or lung tissue. At 60 mg/kg in rat liver, sodium arsenate increased hepatic HO fivefold. MMA decreased ALT at 226 mg/kg, decreased ALT and GSH at 679 mg/kg and also increased P450 at 679 mg/kg in rat liver. DMA decreased ALT and hepatic GSH and increased hepatic HO at 387 mg/kg. In the lung, DMA decreased ODC at both 129 and 387 mg/kg. DD in lung tissue was significantly higher at 387 mg/kg DMA, demonstrating organ specific DNA damage. The biochemical effects and the inferred oncologic potential of the four major forms of arsenic (arsenate, arsenite, MMA and DMA) differ dramatically. The inorganic forms (arsenate and arsenite) are similar to each other (both good HO inducers); the methylated organic forms of arsenic (MMA and DMA) also share a similar pattern of biochemical effects (decreased GSH and ALT, increased P450). All six of the biochemical parameters studied were altered by DMA in either rat liver or lung.

Neonatal deprivation of maternal touch may suppress ornithine decarboxylase via downregulation of the proto-oncogenes c-myc and max

Previously, we have shown that short-term (1 hr) separation of neonatal rats from their mother (MS) suppresses basal ornithine decarboxylase (ODC) synthesis and tissue ODC response to trophic factors. This effect in the pup is caused by absence of maternal tactile stimulation (touch) but not from lack of maternal nutrients (food). This study was performed to examine in 10-d-old rats whether maternal touch deprivation affects expression of certain hepatic proto-oncogenes, the protein products of which are known to interact with the regulatory region of the ODC gene. Prolactin (PRL) injected subcutaneously increased hepatic ODC activity as well as mRNA levels of ODC and the proto-oncogenes c-fos, c-jun, junB, junD, c-myc, and max. MS significantly suppressed PRL-induced increases in ODC enzyme activity and c-myc, max, and ODC mRNAs but had little effect on expression of the other proto-oncogenes. PRL-induced stimulation of ODC, c-myc, and max mRNAs also was depressed in neonates placed with an anesthetized lactating dam (touch-deprived) but not in pups placed with nipple-ligated dams (food-deprived). Furthermore, unlike its effect on preweanling-age pups (< 20 d old), MS did not alter expression of either ODC or c-myc mRNAs in 25-d-old pups acutely separated from their mother. These findings indicate that suppression of ODC gene transcription in the neonatal pup during MS may be mediated by downregulation of the ODC gene transactivator proto-oncogenes c-myc and max. They are also consistent with our previous observation that lack of maternal touch, but not maternal milk, initiates the physiological alterations induced by MS.

Arsenite, but not cadmium, induces ornithine decarboxylase and heme oxygenase activity in rat liver: relevance to arsenic carcinogenesis

Sodium arsenite and cadmium chloride, were administered orally to adult female rats at 21 and 4 h prior to sacrifice. Liver, lung, skin and urinary bladder were the tissues studied. DNA damage, cytochrome P450, glutathione content (GSH), ornithine decarboxylase (ODC), serum alanine aminotransferase and heme oxygenase activity were measured. Sodium arsenite increased rat hepatic ODC activity at 1.6 and 24.6 mg/kg and hepatic heme oxygenase activity at 8.2 and 24.6 mg/kg, but did not cause any DNA damage. Cadmium chloride did not affect any of the six parameters tested. These findings suggest that sodium arsenite may be a promoter rather than an initiator of carcinogenesis.

Growth-Promoting Potential and Toxicity of Spermidine, a Polyamine and Biogenic Amine Found in Foods and Feedstuffs

Experiments were conducted to determine the relative growth-promoting potential and toxicity of dietary spermidine, a biogenic amine and polyamine. Week-old chicks were fed purified diets containing 0.0, 0.2, 0.4, 0.6, 0.8, or 1.0% supplemental spermidine for 2 weeks. As little as 0.4% supplemental spermidine depressed growth and hepatic ornithine decarboxylase activity, while hepatic concentrations of putrescine, spermidine, and N1-acetylspermidine increased. In a second experiment, 0.00, 0.05, 0.10, 0.20, and 0.60% supplemental spermidine were fed. Low levels of supplemental spermidine tended to increase relative weights of the duodenum and pancreas. The temporal response to 0.00, 0.05, and 0.60% supplemental spermidine was determined in a third experiment when measurements were taken following 1, 2, 4, and 8 days of feeding. Chicks fed diets containing 0.05% supplemental spermidine had increased growth after only 1 day of feeding. Enlargement of the duodenum and pancreas was subsequently seen, although these changes became less obvious with time. It was concluded that the toxicity of polyamines increases with molecular weight and charge and, although some growth promotion is possible, the biogenic amine content of suspect feedstuffs should be determined before feeding with caution. Keywords: Spermidine; polyamine; growth; toxicity

Arsenite, but not cadmium, induces ornithine decarboxylase and heme oxygenase activity in rat liver: relevance to arsenic carcinogenesis

Sodium arsenite and cadmium chloride, were administered orally to adult female rats at 21 and 4 h prior to sacrifice. Liver, lung, skin and urinary bladder were the tissues studied. DNA damage, cytochrome P450, glutathione content (GSH), ornithine decarboxylase (ODC), serum alanine aminotransferase and heme oxygenase activity were measured. Sodium arsenite increased rat hepatic ODC activity at 1.6 and 24.6 mg/kg and hepatic heme oxygenase activity at 8.2 and 24.6 mg/kg, but did not cause any DNA damage. Cadmium chloride did not affect any of the six parameters tested. These findings suggest that sodium arsenite may be a promoter rather than an initiator of carcinogenesis.

The differential effects of three forms of interferon alfa on hepatic regeneration after partial hepatectomy in the rat

The purpose of this study was to determine whether all commercially available forms of interferon alfa (INF alpha) have the same inhibitory effect on hepatic regeneration and whether this inhibitory effect can be prevented by putrescine, a hepatic growth promotor. Adult male Sprague-Dawley rats (n = 92) received either IFN alpha-2a, 2b, n1, or saline, 0 and 18 hours after partial hepatectomy (PHx) or 16 hours before PHx. A subgroup of 29 rats being treated with IFn alpha-2a or saline also received putrescine (5, 50, or 500 mg/kg) 16 hours before PHx. Hepatic regeneration was documented by determining [3H]-thymidine incorporation into hepatic DNA (DNA synthesis), hepatic putrescine levels, and, in selected cases, ornithine decarboxylase (ODC) activity at 24 hours after PHx. The results of the study showed that hepatic regeneration was unaffected when IFN alpha was administered 0 and 18 hours after PHx. When administered at -16 hours, only IFN alpha-2a significantly inhibited DNA synthesis and was associated with decreased hepatic putrescine levels. Inhibition was dose-dependent in that a 10-fold increase in IFN alpha-2a caused a further decrease in both DNA synthesis and hepatic putrescine levels. At the higher dose, IFN alpha-2b and n1 also inhibited DNA synthesis and lowered hepatic putrescine levels and ODC activity. Exogenous putrescine (5 and 50 mg/kg) restored hepatic regenerative activity to normal but was toxic at high concentrations (500 mg/kg). These data indicate that not all commercially available forms of IFN alpha inhibit hepatic regeneration in the rat to the same extent.