Liver Ornithine Decarboxylase Research Articles

Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.

INPACT OF LAPONITE ON ENZYME ACTIVITY AND REDOX STATE OF THE TUMOR AND ORGANS OF THE DETOXIFICATION SYSTEM OF MICE WITH EhRLICH CARCINOMA

Summary. Laponite (Lap) is a synthetic clay mineral represented by disk-shaped nanoplatelets. The Lap (native or acid-activated) can be used for encapsulation of medical compounds, in particular anticancer drugs. Aim: to study the levels of the rate of superoxide radical (SR) generation, the activity of ribonucleases (RNases), gelatinases and ornithine decarboxylase (ODK) in tumor cells, liver and kidneys of intact mice and mice with Ehrlich carcinoma under the influence of Lap. Objects and methods: the purified gel-forming native Lap of the XLG class with the empirical formula Si8Mg5.45Li0.4H4O24Na0.7 was used. Acid activation of Lap (aLap samples) was done using sulfuric acid. The laboratory experiments were performed using outbred mice with transplanted Ehrlich carcinoma in ascites and solid forms. Determination of the rate of generation of SR was carried out by the method of electron paramagnetic resonance, RNases and matrix metalloproteinases activities were determined zymography in polyacrylamide gel, ODC activity was determined spectrophotometrically, statistical analysis of the results was performed using Student’s t-test. Results: the data on the rate of the superoxide generation and the activity of gelatinases in the liver tissue, the tumor tissue and the ascites fluid Ehrlich carcinoma were compared. The introducing of native Lap resulted in noticeable decrease in the rate of the superoxide generation in the liver tissue by 1.7 times as compared with the control group of mice, and in the ascites fluid by 1.5 times as compared with the mice group without Lap. Moreover, introducing of native Lap resulted in the decrease of the gelatinases activity by 2.4 times in the ascites fluid and 1.9 times in the solid Ehrlich carcinoma tissue. The less significant effects were observed for samples with incorporated aLap. No significant difference was found between the indicators of RNase and ODC activities under the influence of native Lap and aLap in intact and tumour-bearing mice. Conclusion: in a model experiment on outbred mice with Ehrlich carcinoma, it was determined that native Lap and aLap do not significantly affect the indicators of the redox state, the activity of RNases, gelatinases and ODC in tumor cells, liver and kidneys. It indicates the safety of using of these nanoplatelets for assistance of anticancer drug delivery.

Assessment of Liver Regeneration in Patients Who Have Undergone Living Donor Hepatectomy for Living Donor Liver Transplantation.

Inflammation and the associated immune pathways are among the most important factors in liver regeneration after living donor hepatectomy. Various biomarkers, especially liver function tests, are used to show liver regeneration. The aim of this study was to evaluate the course of liver regeneration following donor hepatectomy (LDH) by routine and regeneration-related biomarkers. Data from 63 living liver donors (LLDs) who underwent LDH in Inonu University Liver Transplant Institute were prospectively analyzed. Serum samples were obtained on the preoperative day and postoperative days (POD) 1, 3, 5, 10, and 21. Regenerative markers including alfa-fetoprotein (AFP), des carboxy prothrombin (DCP), ornithine decarboxylase (ODC), retinol-binding protein 4 (RBP4), and angiotensin-converting enzyme isotype II (ACEII) and liver function tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and total bilirubin levels were all analyzed. The median age of the LLDs was 29.7 years and 28 LLDs were female. Eight LLDs developed postoperative complications requiring relaparotomy. The routine laboratory parameters including AST (<0.001), ALT (<0.001), ALP (<0.001), and total bilirubin (<0.001) showed a significant increase over time until postoperative day (POD) 3. For the regeneration-related parameters, except for the RBP4, all parameters including ACEII (p = 0.006), AFP (p = 0.002), DCP (p = 0.007), and ODC (p = 0.002) showed a significant increase in POD3. The regeneration parameters showed a different pattern of change. In right-lobe liver grafts, ACEII (p = 0.002), AFP (p = 0.035), and ODC (p = 0.001) showed a significant increase over time. DCP (p = 0.129) and RBP4 (p = 0.335) showed no significant changes in right-lobe liver grafts. Regenerative markers are increased in a sustained fashion following LDH. This is more prominent following right-lobe grafts which are indicative of progenitor-associated liver regeneration.

Adult Atlantic salmon (Salmo salarL.) adapts to long-term surplus dietary arginine supplementation

The current study aimed to investigate the effect of surplus dietary arginine on polyamine and amino acid metabolism and accretion of proteins and lipids, as previous studies have demonstrated a lipid-reducing effect following surplus arginine supplementation in viscera as well as increased muscle growth. Four plant protein-based diets were given increasing concentrations of L-arginine, from 21.1 to 36.1 g kg-1 DM, and fed to quadruplicate tanks of adult Atlantic salmon (1.1 kg) for 12 weeks. No effects on growth or deposition of fat or protein were observed. Free amino acid concentrations and related metabolites were unaffected in the liver, except for urea, while concentrations in muscle and plasma reflected production of arginine metabolites. Polyamine concentrations were unaffected in liver, muscle and white adipose tissue (WAT), as were the abundance and activity of spermidine/spermine N1-acetyltransferase (SSAT), the rate-limiting enzyme in polyamine turnover. Gene expression demonstrated differential regulation of ornithine decarboxylase (ODC) in liver and WAT, although overall little effects were observed on gene expression. Liver S-adenosylmethionine (SAM) concentrations decreased with arginine supplementation. We suggest that adult Atlantic salmon have adapted to surplus arginine, and the main long-term effect appears to be increased concentrations of arginine metabolites.

Effect of different thyroid state on ornithine decarboxylase activity and receptors of T3 in rat liver.

The effects of thyreoidectomy, of the administration of 3,5,3'-triiodothyronine (T3), of thyroxine (T4) together with the inhibitor of iodothyronine 5'-deiodinase activity 6-propyl-2-thiouracil (PTU) and of PTU alone on rat liver ornithine decarboxylase (ODC) activity was studied. 28 days after thyroidectomy there was a decrease in ODC activity, whereas T3 treatment of normal rats increased enzyme activity. PTU decreased ODC activity in intact rats and inhibited ODC activity in animals treated with T4. Neither thyroidectomy T3, T4 given in vivo nor the polyamines spermine and spermidine added in vitro influenced the binding of 125I-T3 to its receptor in liver nuclei. Only addition of PTU increased Ka significantly (P less than 0.01). It is concluded that ODC activity in the liver is directly correlated with the thyroid state but not to parameters of thyroid hormone receptor in liver nuclei.

The Skin as a Neurodevelopmental Interface

After completing this article, readers should be able to: 1. Characterize the incidence of severe neurodevelopmental handicaps in very low-birthweight infants over the past decade. 2. Define severe neurodevelopmental deficits. 3. Characterize the derivation of the brain and the epidermis. 4. Describe the possibilities of evoked potential testing for evaluation of brain function in asphyxiated and very low-birthweight preterm infants. 5. Characterize in utero development of the high electrical resistance of skin. “Compared with newborns of other species, the human neonate is relatively helpless in motor capabilities and relatively precocious in sensory capabilities.” —T. Berry Brazelton Behavioral Competence Avery’s Neonatology . 5th ed. 1999 Accumulating evidence suggests a connection between the developing brain and the developing skin. In this view, the skin, broadly considered, functions as a neurodevelopmental boundary in the very low-birthweight (VLBW) preterm infant. The epidermis, for example, plays a role as a specialized ectodermal derivative closely linked to both neuroperception and noninvasive monitoring in intensive care environments. The terminal differentiation product of the epidermis, the stratum corneum, is considered a prototypical smart material. The concept of the skin as a neurodevelopmental interface may be broadened to include its role as an interface with the caregiver and a boundary for primary care delivery in the neonatal intensive care unit. Recent reviews have demonstrated the persistence of a high incidence of severe neurodevelopmental disability in VLBW preterm infants (Fig 1⇓ ). (1) Severe neurodevelopmental disability generally is defined as subnormal cognitive function, cerebral palsy, blindness, deafness, or a combination of these factors. The continuing high incidence of neurodevelopmental handicap raises several questions: 1) Given the complexity and relative inaccessibility of the central nervous system (CNS), is it advantageous to consider alternative viewpoints for the etiology and therapy of neurodevelopmental handicaps? 2) Given the close embryologic connection between brain and skin, should cognition be …

Ornithine decarboxylase and thymidine kinase activities and polyamine levels from selected organs of adult miniature swine receiving three concentrations of dietary menhaden oil

Mature, female swine were randomly assigned to one of seven dietary groups. Swine in groups 1–3 were fed a cholesterol-rich diet for 55 days while the remaining groups remained on a basal swine diet. At the end of the cholesterol(Chol)-preloading period the swine in groups 1–7 were placed on menhaden oil (MO) and/or corn oil (CO) as follows: groups 1 and 4, 15% CO (control); groups 2 and 5, 0.75% MO+14.25% CO; groups 3 and 7, 15% MO; and group 6, 7.5% MO+7.5% CO. Animals were killed at the end of the approximately 6-month feeding period and portions of liver, pancreas and colon mucosa were analyzed for both ornithine decarboxylase (ODC) and thymidine kinase (TK) activity while polyamine levels were measured in the liver and pancreas. Statistical analyses were carried out by one-way and two-way ANOVA and by trend analysis. In the pancreas, the highest MO group (group 7) had significantly higher ODC levels when compared with the CO control (group 4) and the next to highest MO group (group 6) (one-way ANOVA)–all non-cholesterol preloaded groups. Using a two-way ANOVA (Chol-by-MO), liver ODC was significantly lower in the CO control when compared with the lowest and highest MO groups (groups 5 and 7, respectively), again in the non-cholesterol-preloaded animals. In the colon, the swine in the Chol-low MO group (group 2) had significantly lower TK activity than the Chol/CO control group (group 1) and Chol/Hi MO group (group 3) (one-way ANOVA) and also had significantly lower activity than all groups except the CO control (group 4) (two-way ANOVA). Liver acetylputrescine in the lowest and highest MO groups (groups 5 and 7, respectively) was significantly higher than in the CO group (group 4). Liver spermidine in the Chol-Hi MO group (group 3) was significantly higher than the Chol-Lo MO group (group 2), while the highest MO group (group 7) had a statistically higher level than the other non-cholesterol groups (groups 4–6) (one-way ANOVA). Liver spermine was significantly higher in the Chol-Hi MO group (group 3) when compared to the CO control (group 1) and the Chol-Lo MO group (group 2) (one-way ANOVA). Pancreatic putrescine in the CO control (group 4) was significantly higher than all other groups (two-way ANOVA) while spermine from the 2 Chol-MO groups (groups 2 and 3) was higher than the Chol-CO control (group 1) (one-way ANOVA). Using trend analysis, liver TK, putrescine and spermidine increased in the non-cholesterol preloaded groups with increasing dietary MO, similar to the increase seen in ODC. Thus, of the three organs studied, only liver responded to menhaden oil with changes in both ODC itself or some of its metabolic engendered products and thymidine kinase; at least for one of the parameters, ODC, change associated with dietary MO was dependent on whether the swine were preloaded with cholesterol.

Suppression of Chemical Carcinogenesis by Water-Soluble Organosulfur Compounds

The chemopreventive effects of five water-soluble organosulfur compounds, S-methylcysteine (SMC) and four analogs, were examined on the promotion stage of diethylnitrosamine hepatocarcinogenesis in male F344 rats, using the medium-term bioassay (Ito test), which is based on the two-step model of hepatocarcinogenesis. In addition, we investigated the modifying effects of SMC and cysteine on the initiation stage of rat hepatocarcinogenesis. Carcinogenic potential was scored by comparing the numbers and areas of a putative neoplastic lesion, glutathione S-transferase placental form (GST-P)--positive hepatocellular foci. SMC and cysteine significantly decreased the number and area of GST-P--positive foci when given in the promotion stage of the Ito test. When given during the initiation stage, these two organosulfur compounds also significantly inhibited focus formation. Liver ornithine decarboxylase activity after two thirds partial hepatectomy and the proportion of hepatocytes positive for proliferating cell nuclear antigen significantly decreased the number of aberrant crypt foci in the colon in a multiorgan carcinogenesis bioassay of rats. These results support SMC and cysteine as chemopreventive agents for hepatocarcinogenesis and colon carcinogenesis. Their intake may be of importance for cancer.

Some aspects of hepatic function in feral brown trout, Salmo trutta, living in metal contaminated water.

Brown trout, Salmo trutta, exposed to heavy metals (mainly Cd and Zn) for at least 2 years in the Eagle River, Colorado, were examined for liver size and activity of the growth-promoting enzyme, ornithine decarboxylase (ODC) and compared to trout living in an uncontaminated site. Liver-somatic index (LSI) was greater for trout living in the uncontaminated site with the LSI of females being significantly greater than that of males. The LSI for females at the uncontaminated site was greater than that of females at the contaminated site, but males were not different statistically. ODC activity in the livers of both males and females was lower at the contaminated site. However, males and females did not differ with respect to ODC activity. These data suggest that chronic exposure to heavy metals may have important implications for growth and reproduction and possibly survival. The activity of ODC in liver might serve as a useful biomarker when assessing chronic toxicity of metals to naturally reproducing fish populations.

Conjugated Linoleic Acids Exhibit a Strong Fat-to-Lean Partitioning Effect, Reduce Serum VLDL Lipids and Redistribute Tissue Lipids in Food-Restricted Rats

Effects of conjugated linoleic acids (CLA) on a series of metabolic events are expected to depend on the feeding regimen and levels of energy ingested. This study was the first examining the mode of action of CLA on body composition, tissue lipids, lipoproteins and hepatic enzymes in situations of enhanced fat store mobilization. Two groups of male growing Sprague-Dawley rats were fed for 3 wk a diet containing 0 (control group) or 3 g/100 g of a CLA mixture at the expense of sunflower oil, and were then subjected to a weight-loss feeding regimen for another 18 d. Rats fed the CLA-fortified diet gained 11% less weight than the control rats (P<0.05). Rats fed the high CLA diet had less body fat (1.47+/-0.16 vs. 1.07+/-0.09 g/100g, P<0.05) and a higher lean deposition (25.6+/-0.2 vs. 28.4+/-0.3 g/100 g, P<0.05) than control rats. CLA-fed rats had a 41% lower cholesterol concentration in liver than the control rats (P<0.05). Some differences in glycerophospholipid subclass profile of liver and erythrocyte membrane were observed; the hepatic concentrations of phosphatidylethanolamine (4.76+/-0.46 vs. 6.86+/-0.99 micromol/g, P = 0.07) and phosphatidylcholine (12.9+/-0.5 vs. 15.3+/-1.2 micromol/g, P = 0.09) tended to be greater and the level of phosphatidylcholine in erythrocyte membranes was significantly greater (1.40+/-0.12 vs. 1.83 +/-0.16 micromol/g, P<0.05) in the CLA-treated group than in the control group. The activities of catalase and ornithine decarboxylase in liver did not differ between the groups. Further, CLA-treated rats had significantly lower serum concentrations of VLDL lipids than control rats, whereas concentrations of LDL and HDL lipids were unaffected. The results indicate that a high dose of a CLA mixture is a strong repartitioning agent and a modulator of lipid metabolism under conditions of enhanced fat store mobilization in rats.

Characterization of Arginine Decarboxylase in Rat Brain and Liver

We compared the properties of mammalian arginine decarboxylase (ADC) and ornithine decarboxylase (ODC) in rat liver and brain. Mammalian ADC is thermally unstable and associated with mitochondrial membranes. ADC decarboxylates both arginine (Km = 0.75 mM) and ornithine (Km = 0.25 mM), a reaction not inhibited by the specific ODC inhibitor, difluoromethylomithine. ADC activity is inhibited by Ca2+, Co2+, and polyamines, is present in many organs being highest in aorta and lowest in testis, and is not recognized by a specific monoclonal antibody to ODC. In contrast, ODC is thermally stable, cytosolic, and mitochondrial and is expressed at low levels in most organs except testis. Although ADC and ODC are expressed in cultured rat C6 glioma cells, the patterns of expression during growth and confluence are very different. We conclude that mammalian ADC differs from ADC isoforms expressed in plants, bacteria, or Caenorhabditis elegans and is distinct from ODC. ADC serves to synthesize agmatine in proximity to mitochondria, an organelle also harboring agmatine's degradative enzyme, agmatinase, and a class of imidazoline receptor (I2) to which agmatine binds with high affinity.

Glucocorticoid regulation of ornithine decarboxylase in the postnatal rat lung

Ornithine decarboxylase (ODC) is thought to play a critical role in pulmonary development. The purpose of this study was to characterize the effects of dexamethasone on ODC gene expression and enzyme activity in the lung of rat pups. Subcutaneous administration of dexamethasone (10 mg kg ) was shown to suppress ODC activity in 2-, 6- and 10-day-old rats for as long as 24 h after injection. In contrast, dexamethasone treatment stimulated liver ODC activity indicating that the inhibition of lung ODC is tissue specific. Contrary to expectation, the glucocorticoid enhanced lung ODC expression as indicated by an increased accumulation of ODC mRNA transcripts. The latter effect was associated with an heightened expression of c-myc and max mRNAs, the encoded proteins of which act as transactivators of the ODC gene. Dexamethasone did not alter lung levels of “antizyme” (AZ), an inducible protein that specifically promotes the degradation of the ODC protein enzyme. However, the lack of AZ induction does not necessarily mean that ODC degradation is not the mechanism for the decrease in lung ODC activity of dexamethasone-treated animals. The results obtained indicate that glucocorticoids can downregulate lung ODC activity, and that the effect is mediated by post-transcriptional rather than transcriptional mechanisms. These findings are consistent with the idea that endogenous glucocorticoids play an important role in the modulation of ODC activity and early pulmonary development.

The Effect of Different Doses of Epidermal Growth Factor on Liver Ornithine Decarboxylase and Na-K ATPase Activities in Newborn Rats

1. Ornithine decarboxylase and Na-K ATPase activities were studied in rat livers that were treated with different doses of epidermal growth factor (EGF). 2. The ornithine decarboxylase activities were studied with spectrophotometry, and results were expressed as micromoles of putrescine per hour per milligram of protein. Na-K ATPase activities were studied on the basis of the principle of measuring the amount of inorganic phosphates released by the hydrolysis of ATP, and the results were expressed as micromoles of inorganic phosphate per hour per milligram of protein. 3. When compared with the controls, although the Na-K ATPase activities were decreased at low doses of EGF, their activities were found to be increased at high doses of EGF. On the other hand, there was a positive correlation between ornithine decarboxylase activities and EGF doses. 4. The results of this study suggest that, whereas the decrease in Na-K ATPase activities at low doses of EGF can be due to the utilization of the enzyme, the increase in Na-K ATPase activities at high doses of EGF can be attributed to its enhanced synthesis.

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.

Inhibitory effect of chlorophyllin on diethylnitrosamine and phenobarbital-induced hepatocarcinogenesis in male F344 rats.

Modifying effects of chlorophyllin (CHL) on the diethylnitrosamine (DEN)‐phenobarbital (PB) hepatocarcinogenesis model were examined in rats. Five‐week‐old male F344 rats were divided into 8 groups. Groups 1 through 5 were given i.p. injections of DEN (100 mg/kg body weight) once a week for 3 weeks beginning one week after the start of the experiment, while groups 6 through 8 received vehicle treatment. Groups 1, 2, 3 and 7 received drinking water with 500 ppm PB from one week after the end of carcinogen or vehicle treatment. CHL‐containing diet (2000 ppm) was given to group 2 during the initiation phase and to groups 3 and 5 during the promotion and the post‐initiation phase, respectively. Group 6 was given the experimental diet alone throughout the experiment (24 weeks). Liver neoplasms were present in DEN‐treated groups and PB treatment promoted liver tumorigenesis. The incidences of adenoma in groups 2 and 3 were significantly smaller than in group 1 (P<0.05 and P<0.02), although the reductions in the incidences of liver cell cancer were not significant. The average numbers of liver neoplasms/rat in group 2 were significantly smaller than in group 1 (P<0.05‐P<0.005), Glutathione S‐transferase placental form‐positive foci were also significantly decreased by CHL treatment (P<0.05 and P<0.001). DEN and PB exposure increased liver ornithine decarboxylase activity and this increase was significantly inhibited by feeding of CHL during the initiation phase (P<0.001). These results suggest that CHL is a chemopreventive agent for liver neoplasia.

Effects of Freund's complete adjuvant on the diurnal rhythms of neuroendocrine processes and ornithine decarboxylase activity in various tissues of male rats.

The aim of this study was to investigate the effects of Freund's complete adjuvant (FCA) on the diurnal rhythms of hormonal parameters in serum and ornithine decarboxylase (ODC) activity in various tissues of male rats. On days 1-2 after FCA, increase of ODC activity (used to evaluate the level of activation) was observed in the hypothalamus, pituitary gland, adrenal medulla, adrenal cortex, liver and lymphoid tissues, while the ODC activity in the kidney was reduced. This was accompanied by an increase in serum corticosterone. On days 3-4 after FCA, ODC activity remained elevated in the pituitary gland, liver and lymphoid tissues, while the ODC activity in the testes and pancreas was reduced; kidney ODC activity returned to baseline. This was associated with increased serum levels of prolactin (Prl) and luteinizing hormone, but decreased growth hormone, testosterone and insulin. The increase in ODC activity in the thymus, as well as the reduced ODC activity in the testes and kidney, can be obtained with paraffin. Furthermore, bromocryptine microcapsules (CBLA) reduced the FCA-induced increase of ODC activity in the pituitary gland, liver and lymphoid tissues (days 3-4) but did not affect the changes in other tissues. The increase in ODC activity in the pituitary gland, liver and lymphoid tissues is specific for FCA. A role for Prl in the induction of ODC in liver and lymphoid tissues is suggested by the fact that CBLA suppresses this enhancement.

Transgenic mice expressing the human ornithine decarboxylase gene under the control of mouse metallothionein I promoter

We have generated a transgenic mouse line harbouring the human ornithine decarboxylase gene under the control of mouse metallothionein I promoter. Even in the absence of an exposure to heavy metals, ornithine decarboxylase was over-expressed in heart, testis, brain, and especially in liver, of the transgenic animals. An exposure of the transgenic mice to zinc further enhanced the enzyme activity to a level which in liver represented up to 8000-fold increase in comparison with non-transgenic animals. The striking stimulation of liver ornithine decarboxylase activity upon treatment of the transgenic mice with zinc was accompanied by a nearly 150-fold increase in the hepatic putrescine content as compared with similarly treated non-transgenic animals. Even though the liver putrescine concentration reached that of spermidine and spermine in the transgenic animals, the contents of the higher polyamines only transiently increased upon zinc administration and then returned to the basal level. These findings once again indicate that mammalian cells possess extremely powerful regulatory machinery to prevent an over-accumulation of spermidine and spermine in non-dividing cells, and that very high tissue putrescine concentrations can be tolerated, at least for periods of a few days, with seemingly no phenotypic changes.

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.

Persistent chemopreventive effect of S-adenosyl-L-methionine on the development of liver putative preneoplastic lesions induced by thiobenzamide in diethylnitrosamine-initiated rats.

S-Adenosyl-L-methionine (SAM) is a strong chemopreventive agent of rat liver carcinogenesis. Examination was made to determine whether inhibition by SAM of the development of preneoplastic liver lesions persists to SAM withdrawal in diethylnitrosamine-initiated F344 rats promoted with thiobenzamide (TB). The rats were subjected, 2 weeks after initiation, to 5 weeks feeding with a 0.1% TB diet followed by a TB-free diet for 6 weeks and then a second TB treatment for 3 weeks. SAM (384 micromol/kg/day) was injected i.m. during the first TB cycle (treatment A) or for 6 weeks after the first TB cycle (treatment B). Many gamma-glutamyltranspeptidase (GGT)-positive lesions developed in initiated rats after the first TB cycle. They decreased in number after TB withdrawal, while partial recovery of lesion number and a great increase in volume occurred after the second TB cycle. Liver ornithine decarboxylase (ODC) activity and c-myc and c-Ha-ras mRNAs increased during the TB cycles and returned to normal liver values after TB withdrawal. Number and size of GGT-positive lesions, DNA synthesis of GGT-positive cells, liver ODC activity and c-myc and c-Ha-ras mRNA levels decreased as a consequence of SAM treatment A. The recovery of these parameters, induced by a second TB cycle in rats not treated with SAM, was prevented by SAM treatment B. These results suggest that SAM causes a persistent decrease in growth capacity of preneoplastic liver lesions in rats subjected to a diethylnitrosamine/TB protocol.

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.