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Biomedical subjects

M Kadiiska

Publications and source records attributed to M Kadiiska.

At least 19 recordsLinked to original sources
PubMed2001

Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat.

Mitochondria are thought to play a major role in hepatic oxidative stress associated with alcohol-induced liver injury. Thus, the hypothesis that delivery of the mitochondrial isoform of superoxide dismutase (Mn-SOD) via recombinant adenovirus would reduce alcohol-induced liver injury was tested. Rats were given recombinant adenovirus containing Mn-SOD (Ad.SOD2) or beta-galactosidase (Ad.lacZ) and then fed alcohol enterally for 4 weeks. Mn-SOD expression and activity of Ad.SOD2 in liver mitochondria of infected animals was increased nearly 3-fold compared with Ad.lacZ-infected controls. Mitochondrial glutathione levels in Ad.lacZ-infected animals were decreased after 4 weeks of chronic ethanol, as expected, but were unchanged in Ad.SOD2-infected animals. Alanine aminotransferase was elevated significantly by ethanol, an effect that was prevented by Ad.SOD2. Moreover, pathology (e.g. the sum of steatosis, inflammation, and necrosis) was elevated dramatically by ethanol in Ad.lacZ-treated rats. This effect was also blunted in animals infected with Ad.SOD2. Neutrophil infiltration was increased about 3-fold in livers from both Ad.lacZ- and Ad.SOD2-infected rats by ethanol treatment. Moreover, ESR-detectable free radical adducts in bile were increased about 8-fold by ethanol. Using (13)C-labeled ethanol, it was determined that nearly 60% of total adducts were due to the alpha-hydroxyethyl radical adduct. This increase in radical formation was blocked completely by Ad.SOD2 infection. Furthermore, apoptosis of hepatocytes was increased about 5-fold by ethanol, an effect also blocked by Ad.SOD2. Interestingly, tumor necrosis factor-alpha mRNA was elevated to the same extent in both Ad.lacZ- and Ad.SOD2-infected animals follows ethanol exposure. These data suggest that hepatocyte mitochondrial oxidative stress is involved in alcohol-induced liver damage and likely follows Kupffer cell activation, cytokine production, and neutrophil infiltration. These results also support the hypothesis that mitochondrial oxidant production is a critical factor in parenchymal cell death caused by alcohol.

Adenoviridae↗
PubMed2001

Mechanisms of arsenic-induced cross-tolerance to nickel cytotoxicity, genotoxicity, and apoptosis in rat liver epithelial cells.

The purpose of the present study was to investigate the mechanism of cross-tolerance to nickel in arsenic-transformed cells. Chronic arsenite-exposed (CAsE) cells (TRL 1215 cells, which had been continuously exposed to 0.5 microM arsenite for 20 or more weeks) and control TRL 1215 cells were both exposed to nickel for 24 h, and cell viability was determined by metabolic integrity. The LC(50) for nickel was 608 +/- 32 microM in CAsE cells as compared to 232 +/- 16 microM in control cells, a 2.6-fold increase. CAsE and control cells were treated with 200 microM nickel for 4 h and cellular-free radical production was measured using ESR spectrometry. Hydroxyl radical generation was decreased in CAsE cells. Thiobarbituric acid reactive substances, indicative of lipid peroxidation, and 8-oxo-2'-deoxyguanosine, indicative of oxidative DNA damage, were reduced in CAsE cells. Flow cytometric analysis using Annexin/FITC revealed that nickel-induced apoptosis was reduced in CAsE cells. CAsE cells showed generalized resistance to oxidant-induced toxicity as evidenced by a marked reduction in sensitivity to hydrogen peroxide. Interestingly, intracellular reduced glutathione (GSH) levels were significantly increased in CAsE cells, and when GSH was depleted, CAsE cells lost their nickel resistance. The mechanism of arsenic-induced cross-tolerance to cytotoxicity, genotoxicity, and apoptosis induced by nickel appears related to a generalized resistance to oxidant-induced injury, probably based, at least in part, in increased cellular GSH levels.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Possible role of caspase-3 inhibition in cadmium-induced blockage of apoptosis.

Cadmium (Cd) and chromium (Cr) are human carcinogens. Cr(VI) is taken up into cells and reduced by cellular reductants to the potential DNA damaging species Cr(V), (IV), and (III). Reactive oxygen species and carbon-based radicals may also be produced during Cr reduction. We previously found that Cd blocks Cr-induced apoptosis, which could allow a larger proportion of genetically damaged cells to escape and become transformed. This study helped define the mechanisms of Cd-induced suppression of apoptosis. Chinese hamster ovary (CHO K1-BH4) cells were treated with either Cd (5-20 microM), Cr(VI) (350 microM), or Cd (5-20 microM) plus Cr(VI) (350 microM) for 3 h and then cultured in metal-free media for an additional 48 h at which time DNA was extracted or nuclei were examined to determine apoptosis. Cd markedly reduced Cr-induced DNA fragmentation and reduced the number of Cr-induced apoptotic cell nuclei to control levels. Additional study investigated the biokinetics and cellular metabolism of Cr. Cd did not alter the cellular Cr accumulation and there were no differences in the levels of reduced glutathione, a compound possibly important in Cr reduction and reflective of the cellular reducing environment. The antiapoptotic effect of Cd was not due to diminished cellular reduction of Cr(VI) as assessed by electron-spin resonance determination of the levels of Cr(V). Thus, Cd suppression of Cr-induced apoptosis is not based on altered Cr toxicokinetics or metabolism. In addition to Cr, Cd also inhibited apoptosis induced by hygromycin B and actinomycin D. Cd was a very effective inhibitor of caspase-3 activity, a central mediator of apoptosis, with nontoxic levels of Cd resulting in up to approximately 60% inhibition. These results indicate that Cd may have a generalized inhibitory effect on apoptosis, possibly by inhibiting caspase-3. Inhibition of apoptosis by Cd may allow a greater portion of genetically damaged cells to survive, or give selective growth advantages, and has implications as a potential nongenotoxic mechanism of Cd carcinogenesis.

Animals↗
PubMed1998

The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury.

Previous research from this laboratory using a continuous enteral ethanol (EtOH) administration model demonstrated that Kupffer cells are pivotal in the development of EtOH-induced liver injury. When Kupffer cells were destroyed using gadolinium chloride (GdCl3) or the gut was sterilized with polymyxin B and neomycin, early inflammation due to EtOH was blocked. Anti-tumour necrosis factor (TNF)-alpha antibody markedly decreased EtOH-induced liver injury and increased TNF-mRNA. These findings led to the hypothesis that EtOH-induced liver injury involves increases in circulating endotoxin leading to activation of Kupffer cells. Pimonidazole, a nitro-imidazole marker, was used to detect hypoxia in downstream pericentral regions of the lobule. Following one large dose of EtOH or chronic enteral EtOH for 1 month, pimonidazole binding was increased significantly in pericentral regions of the liver lobule, which was diminished with GdCl3. Enteral EtOH increased free radical generation detected with electron spin resonance (ESR). These radical species had coupling constants matching alpha-hydroxyethyl radical and were shown conclusively to arise from EtOH based on a doubling of the ESR lines when 13C-EtOH was given. Alpha-hydroxyethyl radical production was also blocked by the destruction of Kupffer cells with GdCl3. It is known that females develop more severe EtOH-induced liver injury more rapidly and with less EtOH than males. Female rats on the enteral protocol exhibited more rapid injury and more widespread fatty changes over a larger portion of the liver lobule than males. Plasma endotoxin, ICAM-1, free radical adducts, infiltrating neutrophils and transcription factor NFkappaB were approximately two-fold greater in livers from females than males after 4 weeks of enteral EtOH treatment. Furthermore, oestrogen treatment increased the sensitivity of Kupffer cells to endotoxin. These data are consistent with the hypothesis that Kupffer cells participate in important gender differences in liver injury caused by ethanol.

Animals↗
PubMed1996

Detection of alpha-hydroxyethyl free radical adducts in the pancreas after chronic exposure to alcohol in the rat.

Chronic pancreatitis is characterized by inflammation and fibrosis leading to tissue destruction; in industrialized nations, alcohol abuse is the cause of 70-80% of cases of pancreatitis in adults. The purpose of the current work was to determine whether free radical adducts are produced by the pancreas during the early phases of chronic exposure to ethanol. Accordingly, rats were chronically fed ethanol using the model of continuous enteral infusion developed by Tsukamoto et al.[Am. J. Physiol. 247: R595-R599 (1984)]. Histological evaluation revealed only mild acinar steatosis and spotty necrosis after 4 weeks of alcohol treatment; the pancreatic enzymes lipase and amylase were not elevated. Furthermore, no fibrosis was detected, nor were there differences in pancreatic collagen alpha 1(l) mRNA levels between the dietary control and ethanol-treated groups. After 4 weeks, rats were injected with the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (1 g/kg intravenously), and pancreatic secretions were collected over a 4-hr period. A six-line free radical adduct spectrum indicative of a carboncentered free radical was detected in pancreatic secretions and in Folch extracts of pancreatic tissue by electron spin resonance spectroscopy. Control experiments ruled out ex vivo radical formation. This study represents the first detection of radical adducts in pancreatic secretions. When [13C]ethanol (3 g/kg intragastrically) was administered, a definitive 12-line spectrum was detected in pancreatic secretions, demonstrating that the alpha-hydroxyethyl radical adduct was formed in the pancreas from [13C]ethanol. Interestingly, only a six-line signal was detected in tissue extracts under these conditions. Free radicals, therefore, are formed in the pancreas during the early phases of chronic alcohol intake in rats before the development of overt pathology.

Adult↗
PubMed1995

Free radical adducts in the bile of rats treated chronically with intragastric alcohol: inhibition by destruction of Kupffer cells.

Free radical products have previously been detected in rodents after chronic feeding with an ethanol-containing, high-fat diet. The significance of reactive free radical formation in ethanol-induced hepatotoxicity has been difficult to assess because most rodent models exhibit only fatty liver. However, serious hepatic damage resembling clinical alcoholic liver injury (e.g., steatosis, inflammation, and necrosis) occurs in rats after continuous intragastric administration of an ethanol-containing, high-fat diet developed by Tsukamoto and French. Accordingly, rats treated with ethanol for at least 2 weeks using this protocol were administered the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone, and bile samples were collected. A six-line radical adduct spectrum was detected in the bile of ethanol-treated rats. A similar spectrum of lower intensity was detected with rats fed a high-fat diet without ethanol, but little or no radical adduct signal was detected with chow-fed animals. For both treatment groups, alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone and extra ethanol were given acutely. Destruction of Kupffer cells by chronic treatment with GdCl3 decreased by about 50% the radical adduct formation in rats fed the ethanol-containing, high-fat diet. This radical species was largely ethanol derived, because addition of [13C]ethanol produced a 12-line spectrum, indicating the formation of alpha-hydroxyethyl radical. Ethanol treatment also caused hypoxia (detected on the liver surface in vivo with oxygen electrodes), which was reflected in a dose-dependent decrease in oxygen tension with ethanol. The effect was blocked by GdCl3. Hepatic damage detected by histology was prevalent in ethanol-treated rats but only mild fatty liver was observed in high-fat diet-fed controls. GdCl3 treatment eliminated hepatic damage due to high-fat and ethanol diets, and when all groups were compared a significant correlation between liver injury and radical adduct signal was observed. Thus, free radical formation in ethanol-treated rats has been detected for the first time in a model that exhibits injury characteristic of human alcoholic injury, and signal intensity correlates with hepatotoxicity. Moreover, the decrease in both free radical formation and hepatic damage produced by GdCl3 implicates Kupffer cells in the development of alcoholic liver injury. This important pathophysiological process may involve direct production of reactive oxygen species or indirect actions of mediators on parenchymal cells.

Animals↗
PubMed1991

Effect of continuous treatment with some heavy metal salts upon rat hepatic monooxygenases.

The effect of 90-days treatment with Co(NO3)2, NiSO4, CdSO4, ZnSO4 and HgCL2 on the rat liver cytochrome P-450 linked monooxygenases was studied. It was found that all metal salts studied significantly decreased the activity of ethylmorphine N-demethylase in the rat liver. The activity of benzphetamine N-demethylase was decreased by the salts of Co, Cd and Zn whereas Hg and Ni did not change it. Hepatic microsomal cytochrome P-450 content was significantly decreased after treatment with Co, Cd, Zn and Ni and was not changed by Hg. Microsomal hem content was decreased by Co, Cd and Zn and was not changed by Ni and Hg. Co, Cd, Zn and Ni salts decreased the activity of 5-aminolevulinic acid synthetase which shows that the decreased cytochrome P-450 content was probably due to a decrease of its synthesis. HgCL2 had no enzyme inhibitory effect. All metal salts did not change the metabolizing activity of aniline hydroxylase which confirm that multiple molecule species of cytochrome P-450 exist in the liver of adult rats. The hepatic cytochrome b5 content was not changed by the metal salts studied which shows that probably cytochrome b5 was not involved in the enzyme inhibitory action of heavy metal salts on the rat liver monooxygenases.

5-Aminolevulinate Synthetase↗
PubMed1990

Effect of subchronic treatment with some heavy metal salts on the activity of the drug metabolizing enzyme system in female rats.

In experiments on female albino rats the effect of 30-day treatment with salts of Co, Cd, Ni, Zn and Hg on the liver monooxygenase system was studied. It was found that CdCl2 and HgCl2 significantly decreased the activity of aniline hydroxylase whereas the activity of ethylmorphine-N-demethylase tended to remain almost constant and no significant changes were observed. The cytochrome P-450 level in Zn-treated female rats was decreased while the other metal salts did not change it. The cytochrome b5 levels were relatively stable and there were no significant differences between treated and untreated animals. Co, Cd and Hg decreased the NADPH-dependent lipid peroxidation whereas Ni and Zn did not change it. All metal salts caused no marked alterations in the female rat liver microsomal membrane fluidity.

Animals↗
PubMed1985

Effect of some heavy metal salts on hepatic monooxygenases after subchronic exposure.

The effects of subchronic exposure of some heavy metal salts on the activity of the rat liver monooxygenases and NADPH-dependent lipid peroxidation have been studied. The salts of Co, Cd and Zn (when given repeatedly for one month in subtoxic doses) shortened the duration of hexobarbital sleeping time, increased the activities of Ethylmorphine-N-demethylase (EMD) and Benzphetamine-N-demethylase (BND), and the cytochrome P-450 and heme contents. The same metal salts increased the activity of delta-aminolevulinic acid synthetase (ALAS), decreased that of Heme-oxygenase and decreased NADPH-dependent lipid peroxidation. Whereas the salts of Co, Cd and Zn seem to exert an enzyme-inducing action on the mixed function oxidizing enzyme systems, the salts of Hg and Ni did not show such effects.

5-Aminolevulinate Synthetase↗
PubMed1985

On the mechanism of the enzyme-inducing action of some heavy metal salts.

The effect of Co(NO3)2, CdSO4, NiSO4, ZnSO4, and HgCl2 (given repeatedly in subtoxic doses in the drinking water for 30 days) on rat liver monooxygenases was studied in experiments on male Wistar rats. The salts of Co, Cd, and Zn increased the activity of benzphetamine-N-demethylase, the content of cytochrome P-450 and microsomal heme. The data suggest that these salts exert an enzyme-inducing effect on the hepatic monooxygenases. The same metal salts (Co, Cd, and Zn) increased the activity of delta-aminolevulinic acid (ALA) synthetase and decreased that of heme oxygenase. The increased cytochrome P-450 content is probably due to the increased synthesis and the decreased breakdown of this hemoprotein. HgCl2 and NiSO4 did not exert an enzyme-inducing action. The lack of change in the activity of NADPH-cytochrome c reductase and cytochrome b5 (except for ZnSO4) suggests that these components of the electron transport chain are not likely to be involved in the enzyme-inducing action of the heavy metal salts.

5-Aminolevulinate Synthetase↗
PubMed1985

Effect of heavy metal salts on rat brain and liver monoamine oxidase activity.

In experiments on male Wistar albino rats was studied the effect of Co, Cd, Ni, Zn, Hg and Pb on the activity of rat liver and brain monoamine oxidase (MAO) using tyramine, serotonin and beta-phenylethylamine as substrates. It was established that ZnSO4 significantly increased the activity of liver MAO with all substrates studied, Co(NO3)2 increased it when tyramine and serotonin were used while NiSO4 increased MAO activity when serotonin was used as a substrate. All metals studied did not change MAO activity in the brain except for Co(NO3)2 which significantly increased the enzyme activity with tyramine as a substrate. The activity of liver MAO proved to be more susceptible to heavy metals after subchronic exposure than that in the whole brain.

Animals↗
PubMed1984

Changes in rat liver and brain monoamine oxidase activity after acute treatment with some heavy metal salts.

In in vivo and in vitro experiments the effects of some heavy metal salts (Cu, Co, Cd, Pb, Ni, Zn, Hg, As, Bi and Sn) on rat liver and brain mitochondrial monoamine oxidase (MAO) activity was studied using three different substrates (tyramine, 5-hydroxytryptamine (5-HT) and beta-phenylethylamine (2-PEA). It was established that some of the metals (Cu, Cd, Bi) inhibited MAO activity both in vivo and in vitro experiments, others like Ni, Zn, As and Sn inhibited it only in vivo while Hg exerted inhibitory action only in vitro. The in vivo experiments showed significantly higher sensitivity of brain MAO as compared with liver MAO to the inhibitory action of metals. The same higher susceptibility was shown by liver and brain MAO-A form. It was concluded that the inhibitory effects of some heavy metal salts on MAO activity were not directly connected with their action on enzyme thiol groups but more probably with changes in the enzyme membrane surroundings in the different organs.

Animals↗
PubMed1984

Hepatic mixed-function oxidase system and microsomal lipid peroxidation in rats treated with a synthetic immunomodulator, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP).

Effects of synthetic muramyl dipeptide (MDP) on activity of liver microsomal mixed-function oxidase system and on the susceptibility of liver microsomes to lipid peroxidation, were tested in rats at intervals of 1 or 24 hours after single i.p. injection of MDP (1 mg per animal). No significant changes were found in levels of cytochrome P-450 and b5, microsomal heme, or in activities of aniline hydroxylase, ethylmorphine demethylase, glucuronide transferase or cytosol glutathione-S-transferase. However, significantly less (about 45%) TBA-reactive material accumulated in microsomal samples at the 1 h-interval after the MDP administration. The same inhibitory effect of MDP on lipid peroxidation was shown in vitro (in 1 mM concentration) after incubation of microsomes with the NADPH/ADP/Fe system.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1983

Heavy metals and enzyme induction.

In experiments on male albino rats it was established that single toxic doses of heavy metal salts inhibited to a different extent the enzyme-inducing action of phenobarbital and methylcholanthrene as determined by ethylmorphine-N-demethylase, respectively aniline hydroxylase activity. The majority of salts (of Cu, Co, Cd, Pb, Ni, Zn and Hg) inhibited more strongly the enzyme induction produced by methylcholanthrene as compared with that caused by phenobarbital. Subtoxic doses of Co, Cd, Zn and Ni salts given daily with the drinking water for 30 days shortened the hexobarbital sleeping time and increased the ethylmorphine-N-demethylase activity and cytochrome P-450 content in the liver microsomes. This suggests an enzyme-inducing action of these heavy metal salts at oral administration in subtoxic doses. Cu, Bi, Sn, Pb did not produce enzyme induction. The changes in the three indices of the As and Hg action were not consistent in our experiments.

Animals↗