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PubMed2000

DNA polymerases and Ki-67 nuclear antigen are induced in correlation with the resected mass of rat liver up to 90%.

BACKGROUND AND AIMS: We studied the regeneration potential by measuring induction of DNA polymerases in the remnant rat liver after a partial hepatectomy (PHx) that is maximal but compatible with survival. METHODS: The regenerating rat liver was obtained after the 90% PHx. The induction of activities of DNA polymerase alpha, delta, and epsilon were measured after partial purification. The Ki-67 nuclear antigen was also detected histochemically. These parameters were compared with those after both 30% and 70% PHx. RESULTS: The 90% hepatectomy resulted in the strong inductions of DNA polymerase alpha, delta, and epsilon, at 48 h after operation, in association with increases in wet weight and total DNA in the remnant liver. The enzyme induction was much higher after 90% PHx than after 30% and 70% hepatectomy, in correlation with the resection volume. At 48 h after 90% hepatectomy, the Ki-67 positive cells increased up to 47.2% of hepatocytes in the remnant liver. CONCLUSION: The higher induction of replication enzymes by 90% hepatectomy reflects more cells entering mitogenic cell cycle, which supports the fast regeneration of the remnant liver. The number of proliferating hepatocytes is stringently controlled by an unknown mechanism sensing the mass of resected liver parenchyma.

Animals↗
PubMed1976

Kinetics of methoxyflurane biotransformation with reference to substrate inhibition.

The kinetics of biotransformation of methoxyflurane by rat hepatic microsomes in vitro was studied. The rate of biotransformation as measured by analysis of metabolites continued to increase even at near-saturation concentrations of the anesthetic. Methoxyflurane biotransformation followed either an unbounded curve with empirical formula y = a ln(bx + 1) or an asymptotic curve with formula (see article) No substrate inhibition was observed. Total fluoride Vmax of 135.1 mmumol F-/mg protein/30' was increased to 931.9 by phenobarbital induction; free fluoride Vmax from 39.2 to 403.2. Thus, enzyme induction shifted biotransformation to the production of greater amounts of inorganic free fluoride metabolites than organic fluoride-containing metabolites. Phenobarbital induction caused qualitative as well as quantitative alteration in the biotransformation of methoxyflurane.

Anesthesia, Inhalation↗
PubMed1976

Aryl hydrocarbon hydroxylase and 16alpha-hydroxylase in cultured human lymphocytes.

Aryl hydrocarbon hydroxylase and 16alpha-hydroxylase were examined in intact, cultured human lymphocytes. The two microsomal mixed-function oxygenases had different pH optima and showed competitive inhibition for enzyme induction and activity. Population distributions were lognormal for both enzymes, giving apparent evidence for polygenic control. Induced levels of AHH were slightly higher among first-order relatives of lung or colon cancer patients than in the control group. The correlation coefficient (r) for AHH and SAH coinducibility was -0.08, indicating no correlation and suggesting the absence of association between the two enzymes in man.

Aryl Hydrocarbon Hydroxylases↗
PubMed1962

Alkaline phosphatase content and the effects of prednisolone on mammalian cells in culture.

The alkaline phosphatase content of different tissue culture cell lines has been shown to vary from no detectable activity to high enzyme concentration. Within the epithelial lines studied alkaline phosphatase is either constitutive or inducible. Two epithelial cell strains in which alkaline phosphatase was "absent" could be induced to develop significant amounts of the enzyme when grown in the presence of Delta(1)-hydrocortisone. Phosphate did not repress enzyme induction by prednisolone. Under conditions of deadaptation the induced enzyme was diluted by cell multiplication. The mouse fibroblastic L line and several human fibroblastic lines did not contain alkaline phosphatase when grown under the conditions described nor could they be induced to produce the enzyme when cultivated in medium with prednisolone. Delta(1)-Hydrocortisone has other characteristic effects on established mammalian cell cultures which vary among cell lines. Human epithelial lines show reduction in cell multiplication with increase in mitotic index. The cytoplasm is increased and cell volume is nearly doubled. Mouse fibroblasts show a similar reduction in cell multiplication with a decrease in mitotic index. There is no increase in cell cytoplasm. Human fibroblast strains show no inhibition of multiplication or alteration in total cell protein when grown in medium containing prednisolone. Antisera prepared against "negative" prednisolone-inducible human cell lines and against a positive human line inhibited alkaline phosphatase activity to an equal degree.

Alkaline Phosphatase↗
PubMed1972

Induction and characterization of -galactosidase in an extreme thermophile.

A thermostable beta-galactosidase (EC 3.2.1.23; beta-dgalactoside galactohydrolase) was found to be inducible in an extreme thermophile resembling Thermus aquaticus. Enzyme induction was achieved by the addition of lactose, galactose, or the alpha-galactoside, melibiose, to growing cultures. The addition of glucose to induced cultures had a repressive effect on further enzyme synthesis. The enzyme was purified 78-fold, and the optimum temperature and pH for activity were determined to be 80 C and pH 5.0, respectively. The enzyme was activated by both manganese and ferrous iron. Sulfhydryl activation and thermal stabilization indicate that the thermophilic beta-galactosidase is a sulfhydryl enzyme. Kinetic determinations at 80 C established a K(m) of 2.0 x 10(-3)m for the chromogenic substrate o-nitrophenyl beta-d-galactopyranoside (ONPG) and a K(1) of 7.5 x 10(-3)m for lactose. The Arrhenius energy of activation (for the hydrolysis of ONPG) was calculated to be 13.7 kcal/mole. A molecular weight of 5.7 x 10(5) daltons was estimated by elution of the enzyme from Sephadex 4B.

Acetone↗
PubMed1986

Induction of mixed-function oxidase activity in mouse lymphoid tissues by polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbon (PAH) exposure can cause mixed-function oxidase (MFO) enzyme induction in certain tissues of various organisms. Measurement of such induction might serve as a useful bioindicator of human exposure to PAHs, provided readily obtainable human tissues can be utilized for such measurements. We have investigated the MFO activity in various lymphoid tissues of the C3H mouse as a model system and have studied the effect of systemic PAH treatment on such enzyme activity. An MFO enzyme assay was used to measure the activity of 7-ethoxyresorufin deethylase, an enzyme activity that may be specific for the cytochrome P-448 subset of MFO enzymes (those enzymes that are induced in cells or tissues following PAH administration). Intraperitoneal injection of mice with 180 mg/kg (4.6 mg) benzo[a]pyrene (BaP) or 160 mg/kg (4.0 mg) 3-methylcholanthrene (MC) produced a significant induction in MFO activity in mouse spleen S9 fractions 48 h after the injection. Induction ratios (induced activity/control activity) between 4 and 5 were seen with BaP; MC produced induction ratios of 2.5-3.0. Enzyme activity was not induced in the spleen within 16 h following BaP or MC administration. Other experiments indicated that MFO activity could be induced in thymus cells 48 h after either BaP or MC treatment. Treatment with BaP or MC did produce significant enzyme induction in the liver and lung tissues from the animals both 16 and 48 h after chemical treatment.

Animals↗
PubMed1987

Further studies on the induction of omicron-pyrocatechuic acid carboxylyase in aging cultures of Aspergillus ornatus.

The phenomenon of enzyme induction in aging cultures of Aspergillus ornatus was examined under various conditions of culture and induction. Under standard conditions of culture on buffered-defined medium and 6 h induction with 0.1% tryptophan, the tryptophan-inducible specific activity of the enzyme omicron-pyrocatechuic acid carboxylyase decreased 50% with age while the uninduced level of that enzyme remained constant. Increasing the induction time to 10 h allowed the specific activity of the enzyme from older mats to reach the level of the younger mats, which were not affected by increased exposure time to tryptophan. This effect was also achieved by increasing the concentration of the inducer to 1.0%. The effectual concentration of tryptophan, that body of inducer that actually entered the cell, did not change with age, but the incorporation of labeled tryptophan into de novo protein synthesis was depressed from 23 to 35% in older mats.

Aspergillus↗
PubMed1977

Microbial metabolism of amino alcohols. Control of formation and stability of partially purified ethanolamine ammonia-lyase in Escherichia coli.

Induction of ethanolamine ammonia-lyase formation in Escherichia coli required both the ethanolamine and vitamin B12, and was gratuitous during growth on glycerol. Ethanolamine analogues inhibited enzyme activity and inhibited growth with ethanolamine as the the nitrogen source, but did not act as inducers. Enzyme formation was more rapid when ethanolamine was added to cultures containing vitamin B12 rather than the reverse. Enzyme formation was subject to catabolic repression, glucose and acetate being particularly effective. Chloramphenicol, I-aminopropan 2-01 and 1,3-diaminopropan-2-01 prevented enzyme induction. Ethanolamine ammonia-lyase, resolved from its cobamide coenzyme, was purified 35-fold. The apoenzyme was stable for several days in the presence of ethanolamine, dithiothreitol, glycerol and K+ ions. Enzyme formation therefore requires both substrate and cobamide coenzyme to be present simultaneously as inducers.

Amino Alcohols↗
PubMedDate not supplied

An approach to QSAR of 16-substituted pregnenolones as microsomal enzyme inducers.

In this study, we attempt to correlate quantitatively the structure of eight 16-substituted pregnenolones with microsomal enzyme inducing activity. We also performed some electrostatic potential calculations to get further insight into the properties of these substituents. It was found that pregnenolone-16 alpha-carbonitrile is the most active steroidal inducer among the pregnenolone derivatives tested. The receptor-inducer interaction is facilitated by a favourable electronic effect of the 16 alpha-substituents. The orientation of the electronegative area at position 16 seems to influence activity. Lipophilic and volume effects of the 16 alpha-substituents do not seem to be important for microsomal enzyme induction. However, substituent length has some influence on drug metabolising enzyme activity, probably interfering with receptor-inducer interactions.

Animals↗
PubMed2002

Induction of microsomal epoxide hydrolase by sulfur amino acid deprivation via the pathway of C-Jun N-terminal kinase and its extracellular exposure during cell death.

Microsomal epoxide hydrolase (mEH), an epoxide detoxifying enzyme and putative cell surface autoantigen, is inducible by xenobiotics and by certain pathophysiological conditions (e.g., tumorigenesis and protein-calorie malnutrition). The present study was designed to determine mEH expression in H4IIE cells during cell death initiated by sulfur amino acid deprivation (SAAD) and to identify the signaling pathway for the enzyme induction. SAAD induced cell death at 48-72 h with translocation of Bax to mitochondria and increased mitochondrial permeability with cytochrome c release, both of which were prevented by SB203580 or by dominant-negative JNK1 [JNK1(-)] stable transfection. Caspase-3 activity was only marginally increased by SAAD. Neither genomic DNA fragmentation nor poly(ADP-ribose) polymerase cleavage was observed during SAAD-induced cell death. Thus, SAAD induced cell death independent of caspase activation. This was supported by the observation that benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a general caspase inhibitor, did not prevent cell death. The levels of mEH mRNA and protein were notably increased in cells under SAAD for 48-72 h. The induction of mEH occurred in parallel with cell death. Whereas SAAD-induced cell death resulted from both JNK1 and p38 kinase activation, mEH induction was decreased only by JNK1(-) transfection. Immunocytochemistry revealed that mEH protein was intensely stained in dying cells, cellular fragments and cell debris. Furthermore, the number of cells positive for surface mEH substantially increased by SAAD, as evidenced by flow cytometry analysis. These results demonstrated that SAAD induced nonapoptotic cell death with Bax translocation to mitochondria and mitochondrial cytochrome c release, but not through caspase-3 activation, and that mEH was induced by SAAD via the pathway of JNK1, but not ERK1/2 or p38 kinase, in parallel with cell death.

Amino Acids, Sulfur↗
PubMed1977

[Participation of the adenylate cyclase system in inductive synthesis of acetylcholinesterase in the brain].

The enhancement of the brain acetyl cholinesterase (ACHE) activity in rats by the intraventricular injection of adrenaline or dibutiryl analogue cyclic adenosine-3',5'-monophosphate (cAMP) was shown to be due to the enzyme inductive synthesis. ACHE induction manifests itself more in the subcortical white matter than in the cortex. The stimulating effect of adrenaline on the ACHE activity is suppressed under the beta-adrenoreceptor block, while the cAMP effect remains unchanged. On the contrary, the block of the alpha-adrenoreceptors stimulates the enzyme synthesis induction. The effects of adrenaline and cAMP are of the same direction and are realized through the beta-adrenoreceptors. The enhancement of ACHE activity during the block of the alpha-adrenoreceptors is accounted for by the elimination of their inhibitory influence on the beta-adrenoreceptors.

Acetylcholinesterase↗
PubMed1976

Induction of ornithine decarboxylase in cultured mouse L cells. I. Effects of cellular growth, hormones, and actinomycin D.

The activity of ornithine decarboxylase [EC 4.1.1.17] (ODC) in mouse L cells in the confluent state was induced within 4 hr by cyclic AMP (cAMP) or by insulin. During growth of L cells the concentration of cAMP increased first, then induction of ODC occurred and finally the cell number increased: the levels of cAMP and ODC increased only transitorily and returned to the basal levels when the cells become confluent. In growing cultures, however, the presence of cAMP reduced induction of ODC and cell growth. These results suggest that cAMP is involved in induction of ODC and that its concentration may be important for enzyme induction as well as for cell growth. Actinomycin D with or without these inducers stimulated induction of ODC in L cells, whereas cycloheximide inhibited it, suggesting that these hormones affect the translational level of ODC synthesis. The effect of actinomycin D on induction of ODC was much greater in non-growing cells than in growing cells. It was also found that the half life of ODC was 81 min in non-growing cells and 112 min in growing cells. This suggests that turnover of the enzyme is more rapid in the non-growing than in the growing state and that there may be an RNA fraction which controls its turnover and which also has a very short half life.

Animals↗
PubMed1996

Role of cytokines, tyrosine kinase, and protein kinase C on production of superoxide and induction of scavenging enzymes in human leukocytes.

We investigated the effects of proximal modulators of cytokines, tyrosine kinase (TK), and protein kinase C (PKC) on reactive oxygen species (ROS) generation and the induction of scavenging enzymes, superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) of human neutrophils and lymphocytes, by using IL1-alpha, TNF-alpha, and IFN-gamma and neutralizing antibodies to these cytokines. Inhibitors of TK (ST638 and herbimycin) or PKC (H-7, calphostin, and staurosporine) were also used. The results revealed that both (O2)- generation stimulated by five different agents (opsonized zymosan, A23187, PAF, PMA, and fMLP) and the inductions of all three scavenging enzymes were potentiated by priming with TNF-alpha. In contrast, both (O2)- generation and enzyme induction were attenuated by priming with IL1-alpha, with the exception of PMA-stimulated (O2)- generation. IFN-gamma decreased (O2)- generation but increased scavenging enzyme induction. Antibodies to all three cytokines and all the TK and PKC inhibitors decreased (O2)- stimulated by most agents, but markedly enhanced (O2)- levels stimulated by PAF. Induction of all three enzymes was enhanced equally by low concentrations of each of the three anticytokine antibodies, while each of the TK or PKC inhibitors decreased induction of SOD and GSH-Px and increased catalase induction. These results suggest that both ROS generation and scavenging enzyme induction are controlled in complex ways by the actions of these three proximal mediators. This supports our hypothesis that disturbances in the regulation of early events of cell activation can lead to oxidative tissue injury.

Adult↗
PubMed1998

Tributyltin modulates 3,3',4,4',5-pentachlorobiphenyl (PCB-126)-induced hepatic CYP1A activity in channel catfish, Ictalurus punctatus.

Many harbor estuaries and their tributaries are contaminated with halogenated aromatic hydrocarbons (HAHs) and polycyclic aromatic hydrocarbons (PAHs). Planar congeners of these two classes initiate their toxic effects, including reproductive, developmental, and immunological dysfunction, primarily through the cytosolic arylhydrocabon receptor (Ahr). However, only rarely are aquatic environments contaminated with Ahr-binding contaminants alone. Instead, most are impacted by a variety of pollutants in mixture. Tributyltin (TBT), a common antifouling biocide, is also found in many harbor estuaries and their tributaries. Several reports indicate that TBT inhibits the cytochrome P-4501A system of fish, at least in vitro, and our recent studies with rodents indicate that TBT potentiates PCB-induced CYP1A. However, the effects of TBT on xenobiotic-induced CYP1A activity in aquatic organisms has been virtually unexplored. To this end, channel catfish, Ictalurus punctatus, were exposed to 3,3'4,4',5-pentachlorobiphenyl (PCB-126, PeCB), TBT, or both in combination, with corn oil (CO) serving as the carrier control. Immunoreactive CYP1A protein and ethoxyresorufin O-deethylase (EROD) activity were measured after (1) a single dose of 0.01, 0. 1, or 1 mg/kg of each or both in combination, and (2) 6 injections of 0.017, 1.7, or 17 microg/kg of each (or in combination) given every 3 d over a 16-d period to yield a cumulative dose of 0.01, 0.1, or 1 mg/kg. As expected, PeCB alone, but not TBT, greatly induced these two CYP1A parameters. Low and middle doses of TBT (0.01 and 0.1 mg/kg), but not the high dose, potentiated PeCB-induced activity at these same doses. This effect of TBT was even more pronounced in the repeated exposure study. Furthermore, EROD activity did not always reflect CYP1A protein induction; enzyme activity was inhibited by TBT at doses that potentiated protein induction (0.01 and 0.1 mg/kg). In summary, TBT potentiates PeCB-induced CYP1A in channel catfish at doses that may be considered environmentally relevant.

Animals↗
PubMed1990

Induction of cytochrome P450 by phenobarbital in rat liver visualized by monoclonal antibody immunoelectron microscopy in situ.

A panel of murine monoclonal antibodies was produced against phenobarbital-inducible cytochrome P450-PB of rat liver in order to establish specific immunological tools for studying the induction process in situ by immunoelectron microscopy and in vitro by a novel ELISA. Antibody 573/64 was found to be useful for both approaches. The immunolabeling procedure with protein A-colloidal gold applied to Lowicryl K4M-embedded rat liver revealed the rough ER as the primary site of cytochrome P450-PB induction. This organelle showed the highest labeling density 12 h after administration of phenobarbital while after maximal enzyme induction at day 5 the labeling density was highest in the smooth ER. Maximal increase in cytochrome P450-PB was 21-fold by morphometric analysis and 15-fold by ELISA. In addition, the enzyme apparently does neither recycle through the Golgi apparatus nor is it degraded in lysosomes when maximally induced.

Animals↗
PubMed1979

Induction and catabolite repression of L-rhamnose dehydrogenase in Pullularia pullulans.

The growth of Pullularia pullulans on L-rhamnose (6-deoxy-L-mannose) as the sole carbon source induces the synthesis of L-rhamnose dehydrogenase, a nicotinamide adenine dinucleotide-dependent enzyme that catalyzes the oxidation of the deoxy sugar to L-rhamnonolactone. The enzyme induction is inhibited by cycloheximide, suggesting de novo synthesis. The presence of d-glucose (0.2%) or D-galactose (0.2%) simultaneously with the inducer in the induction medium produced 50% repression of dehydrogenase synthesis, but no effect was detected with D-fructose and D-mannose at the same concentration. High levels of D-glucose (2%), under maximal catabolite repression conditions, produced a complete inhibition of enzyme synthesis.

Carbohydrate Dehydrogenases↗
PubMed1993

Pyruvate stimulates hormonal induction of lipogenic enzymes in primary cultured rat hepatocytes.

Hormonal inductions of lipogenic enzyme activities (fatty acid synthetase, malic enzyme (ME), glucose-6-phosphate dehydrogenase (G6PD) and ATP-citrate lyase) were studied in primary cultured rat hepatocytes. Insulin, triiodothyronine and dexamethasone markedly stimulated the inductions of the enzymes (particularly G6PD and ME) in the presence of pyruvate. Lactate also induced their activities. The activities of these enzymes in the presence of appropriate hormone combinations and a substrate amount of pyruvate were as high as, or higher than those in the liver of rats on high-carbohydrate, low-fat diet. The aldolase and glucokinase activities induced by these hormones were not enhanced by the addition of pyruvate. The induction by pyruvate was inhibited by actinomycin D or cycloheximide. The ATP content of rat hepatocytes was maintained without increase during culture with pyruvate for 6 days. These results indicate that the additions of pyruvate, or its metabolites to cultures of isolated hepatocytes have specific effects on the inductions of certain hepatic enzymes, possibly acting at the level of transcription. Their effects are similar to those of feeding a high-carbohydrate, low-fat diet to intact animals.

ATP Citrate (pro-S)-Lyase↗
PubMed1993

Vitamin E attenuates induction of elastase-like activity by tumor necrosis factor-alpha, cholestan-3 beta,5 alpha,6 beta-triol and linoleic acid in cultured endothelial cells.

Disturbances in arterial wall elastin metabolism appear to be important factors in atherosclerosis development. To evaluate this hypothesis, elastase-like activity was determined in cultured endothelial cells and their surrounding media after exposure to tumor necrosis factor-alpha (TNF), cholestan-3 beta,5 alpha,6 beta-triol (Triol) and linoleic acid (18:2). Significant increases in elastase-like activity both in the cells and in the media were observed when subconfluent endothelial cells were treated with 12 microM Triol, 500 U TNF/ml, or 90 microM 18:2, for 72 h in the presence of 5% calf serum. Even higher activities were measured when endothelial cells were seeded directly into media enriched with 18:2, TNF or Triol and treated for 72 h. Vitamin E supplementation (25 microM) attenuated elastase-like activity in cells and media, independent of treatment. These results suggest that elastase-like enzyme induction in endothelial cells may be involved in cellular perturbations induced by certain lipids and cytokines. Vitamin E may provide a protective function by preventing the induction of elastolytic enzymes. This may have implications in elastin metabolism and atherosclerosis.

Animals↗