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PubMed1989

Characteristics of monocyte angiotensin-converting enzyme (ACE) induction by dexamethasone.

Monocyte maturation to macrophages and transformation into epithelioid granuloma cells in some granulomatous diseases are accompanied by the induction of membrane-bound angiotensin-converting enzyme (ACE). The physiologic and pathophysiologic roles of ACE generated in these processes are not known. The pattern and the mechanism of ACE induction in human monocytes are also not well understood. Dexamethasone is one of the agents reported to induce elevated ACE activity in human monocytes, and therefore a suitable tool for studying the phenomenon. This study shows that dexamethasone augments monocyte ACE in a biphasic dose-dependent manner with maximum effect at 10(-8) M concentration. Although it enhances the level of ACE activity, dexamethasone does not alter the time course for ACE induction from that found in unstimulated monocytes. The ACE activity of monocytes cultivated in 10 nM dexamethasone and then exposed to 10(-3) M diazosulfanilic acid (DASA) is reduced approximately by 80% in comparison with cells not treated with DASA, demonstrating that dexamethasone-induced ACE is an ectoenzyme. Dexamethasone does not increase the activity of other monocyte ectoenzymes: gamma-glutamyltransferase, alkaline phosphodiesterase-I, and leucine aminopeptidase, showing that dexamethasone induction of ACE is a specific, rather than generalized, effect on plasma membrane enzymes. It is suggested that the increase in ACE activity is due to the increased rate of enzyme synthesis.

Dexamethasone↗
PubMed1992

Induction of enzymes involved in fatty acid beta-oxidation in Pseudomonas fragi B-0771 cells grown in media supplemented with fatty acid.

Induction of the enzymes involved in fatty acid beta-oxidation in Pseudomonas fragi B-0771 cells grown in a medium containing straight chain saturated fatty acids was studied. The acyl-CoA dehydrogenase (ACDH) activity was induced during the exponential phase in cells grown in palmitic acid-supplemented medium, reached a maximum at the early stationary phase, and then gradually decreased thereafter. Changes in the overall activities of 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase, both existing on the multienzyme complex (HDT) involved in fatty acid beta-oxidation, were similar to that in ACDH activity. Straight chain saturated fatty acids having more than 6 carbon atoms could induce both the ACDH and HDT activities, and C13-C15 fatty acids caused the greatest induction of both activities. Changes in the overall activities of 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase correlated with that in the amount of the alpha-subunit of HDT during the entire culture period in the medium containing palmitic acid. Surprisingly, the stoichiometry of the alpha- and beta-subunit proteins of HDT was not maintained into the stationary phase culture, though the genes encoding the alpha- and beta-subunits are tandemly coded in bacterial genomic DNA.

Acetyl-CoA C-Acyltransferase↗
PubMed2000

Inhibition of nitric oxide synthase by nasal decongestants.

The nasal decongestants oxymetazoline and xylometazoline are frequently used in the topical treatment of rhinitis and sinusitis. As nitric oxide (NO) is thought to play a role in inflammation of the upper respiratory tract, the aim of this study was to examine the in vitro effects of these compounds on the activity and the expression of NO producing enzymes, including the inducible form of NO synthase (iNOS) and the constitutive isoform of NO synthase (cNOS). Experiments concerning the effects of both compounds on enzymatic activity and enzyme induction of iNOS were performed in a lipopolysaccharide (LPS) induced rat alveolar macrophage cell line (NR8383) using the Griess assay and the 3H-citrulline assay respectively. The effects on cNOS were examined in fresh rat synaptosomes using the 3H-citrulline assay. The direct scavenging properties of both compounds were investigated using a amperometric NO sensor. Oxymetazoline and xylometazoline were shown to have a dose dependent inhibitory effect on total iNOS activity indicated by nitrite/nitrate formation in the Griess assay. This effect was found to be due to an inhibition of induction of the enzyme rather than inhibition of the enzyme activity, as was investigated in two separate experiments using the 3H-citrulline assay. Inhibition of cNOS was moderate and in the same order of magnitude as the inhibition of enzymatic iNOS activity. Direct scavenging of NO could not be detected. As constitutive nitric oxide synthase activity is thought to serve beneficial physiological functions, and exaggerated inducible nitric oxide synthase activity may cause exacerbation of the inflammatory process, pharmacological treatment influencing the nitric oxide generating system should focus on inhibition of inducible nitric oxide synthase alone. The specific characteristics of these decongestants in vitro suggests suitability for this application and may indicate an additional beneficial effect in the treatment of upper respiratory tract inflammation.

Animals↗
PubMed1973

2,3,7,8-Tetrachlorodibenzo-p-dioxin: a potent inducer of -aminolevulinic acid synthetase.

2,3,7,8-Tetrachlorodibenzo-p-dioxin, a toxic contaminant frequently formed during the synthesis of the herbicide 2,4,5-trichlorophenoxyacetic acid, was shown to be a potent inducer of hepatic delta-aminolevulinic acid synthetase in the chick embryo. As little as 4.66 x 10(-12) mole of the contaminant per egg produces a significant increase in the activity of the enzyme. Induction of the enzyme is related to the dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin and, in contrast to that produced with other drugs, is prolonged in time, with 70 percent of the maximum induced activity present 5 days after a single dose. This contaminant is implicated as the likely causative agent in an outbreak of porphyria cutanea tarda in workers in a factory where 2,4,5-trichlorophenoxyacetic acid was being synthesized.

5-Aminolevulinate Synthetase↗
PubMed1981

Enzyme inducer effects after liver denervation in the rat.

The part of liver innervation was studied in the process of microsomal enzyme induction elicited by phenobarbital or muscular exercise. Enzyme induction was seen to develop: hexobarbital sleeping times became shorter after partial (vagotomy, coeliectomy) as well as total liver denervation in the rat. Though the present results did not preclude subtile differences, they demonstrated that the microsomal enzyme systems of the liver could be activated in the absence of innervation. Upper median laparatomy, which was used as a sham operation, had the strange effect of elongating the sleeping time. This observation is a warning of a changed rate of drug elimination after explorative laparatomy.

Animals↗
PubMed1988

Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis.

Carcinogenesis is blocked by an extraordinary variety of agents belonging to many different classes--e.g., phenolic antioxidants, azo dyes, polycyclic aromatics, flavonoids, coumarins, cinnamates, indoles, isothiocyanates, 1,2-dithiol-3-thiones, and thiocarbamates. The only known common property of these anticarcinogens is their ability to elevate in animal cells the activities of enzymes that inactivate the reactive electrophilic forms of carcinogens. Structure-activity studies on the induction of quinone reductase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2] and glutathione S-transferases have revealed that many anti-carcinogenic enzyme inducers contain a distinctive and hitherto unrecognized chemical feature (or acquire this feature after metabolism) that regulates the synthesis of these protective enzymes. The inducers are Michael reaction acceptors characterized by olefinic (or acetylenic) bonds that are rendered electrophilic (positively charged) by conjugation with electron-withdrawing substrates. The potency of inducers parallels their efficiency in Michael reactions. Many inducers are also substrates for glutathione S-transferases, which is further evidence for their electrophilicity. These generalizations have not only provided mechanistic insight into the perplexing question of how such seemingly unrelated anticarcinogens induce chemoprotective enzymes, but also have led to the prediction of the structures of inducers with potential chemoprotective activity.

Acrylates↗
PubMed2004

Steroid hormone biotransformation and xenobiotic induction of hepatic steroid metabolizing enzymes.

Normal reproductive development depends on the interplay of steroid hormones with their receptors at specific tissue sites. The concentrations of hormone ligands in the circulation and at target sites are maintained through coordinated regulation on steroid biosynthesis and degradation. Changed bioavailability of steroids, through alteration of steroidogenesis or biotransformation rates, leads to changes in endocrine function. Steroid hormones lose their receptor reactivity in most cases when they are bound to binding proteins, while metabolic conversion can result in either active or inactive metabolites. Hydroxylation by cytochrome P450 (CYP) enzymes and conjugation with glucuronide and sulfate are among the major hepatic pathways of steroid inactivation. The expression of these biotransformation enzymes can be induced by many xenobiotics. The barbiturate phenobarbital and the environmental toxicant 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) are among the well characterized inducers for the CYP 2B and 3A enzymes and selected conjugation enzymes. The induction of the steroid biotransformation enzymes is partly mediated through the activation of a group of nuclear receptors including the glucocorticoid receptor, the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the peroxisome proliferator activated receptors (PPAR). Drug or chemical-induced increases in hepatic enzyme activities are often a basis for drug-drug interactions that lead to enhanced elimination and reduced therapeutic efficacy of steroidal drugs. The effects of enzyme induction on endogenous steroid clearance, along with its possible consequence, are less well understood. While enzyme induction by xenobiotics may increase clearance of the endogenous steroid, regulatory mechanisms for steroid homeostasis may adapt and compensate for altered clearance.

Animals↗
PubMed1987

Interaction of adrenal and pancreatic hormones in the control of hepatic enzymes during development.

In the liver of suckling rats, the synthesis of hepatic tyrosine aminotransferase, serine dehydratase, and phosphofructokinase 2 as well as of renal beta-glucosidase is controlled by the circulating concentrations of adrenal and pancreatic hormones. Glucagon is capable of stimulating enzyme synthesis only in the presence of a steroid hormone. Dexamethasone and estradiol have been found to exert a permissive function on the inducibility of the studied enzymes by glucagon. Between the hormones of the adrenal medulla and glucagon antagonistic effects in enzyme induction were observed. Obviously, this antagonism is mediated by the alpha 1-adrenergic signal transferring system. A characteristic age dependence of enzyme induction by dexamethasone has been established. This might be correlated to alterations in the degree of methylation of the respective promoters. The methylation inhibitor 5-azacytidine influences significantly the enzyme induction by glucocorticoid hormones.

Adrenal Cortex Hormones↗
PubMed1976

Starch degradation by the mould Trichoderma viride. II. Regulation of enzyme synthesis.

The synthesis of amylolytic enzymes by the maltose not-utilizing Trichoderma viride strain CBS 354.44 requires the presence of starch or dextrins. Several readily utilizable carbon sources such as glucose and glutamic acid were shown to exert a strong catabolite repression which completely inhibited enzyme induction by starch or dextrins. Enzyme synthesis occurs in the exponential and in the stationary growth phase. In the latter, the ratio between saccharifying and dextrinizing enzyme activity is invariably high. In the exponential growth phase this ratio depends on the nature of the inducing substrate. Growth on starch results in an initially high production of dextrinizing activity, the saccharifying one becoming predominant in the course of exponential growth. The latter activity in dextrin DE 30 cultures is predominant from the very beginning. Thus, the amylolytic enzyme system of T. viride consists of at least two different enzymes, the synthesis of each being controlled specifically. The careful regulation of the synthesis of the dextrinizing enzyme is discussed with special reference to the production of non-utilizable maltose by the latter.

Amylases↗
PubMed1989

Protein kinase C and chondrocyte activation.

We have begun to examine the role of protein kinase C (PKC) in chondrocyte activation by interleukin-1 (IL-1) in search of a possible signal transduction mechanism. Untreated chondrocytes synthesised little or no collagenase or gelatinase and only modest amounts of prostaglandin E2 (PGE2), while IL-1 induced considerable amounts of these. An activator of PKC, phorbol myristate acetate (PMA), alone did not influence the synthesis of the metalloproteinases to any great degree, but enhanced PGE2 production. Sphingosine and staurosporin, inhibitors of PKC, each eliminated the synergistic effect of PMA upon enzyme induction by high doses (10 U/ml) of IL-1, but failed to influence enzyme induction by this dose of IL-1 alone. However, a low dose (1 U/ml) of IL-1 in combination with these inhibitors was synergistic upon enzyme induction. Although these inhibitors reduced the synthesis of PGE2 in response to PMA, synthesis of PGE2 in response to both doses of IL-1 was greatly enhanced by the inhibitors. PMA, but not IL-1, enhanced the phosphorylation of an 80 K protein which is characteristic of PKC activity in certain types of cells. From these data, we conclude that PKC is unlikely to be involved in the induction of neutral metalloproteinases by IL-1, although once induction has occurred, PKC may modulate this effect. PKC may also act as regulator of PGE2 synthesis, although this requires further investigation.

Animals↗
PubMed1979

The effect of exposure to halogenated anaesthetics on liver glutathione levels in rats. An index of hepatotoxicity.

Having studied anaesthetic drug interactions in rats, we report the effects of halogenated anaesthetics on the liver glutathione levels and histology, as well as the results of the enhancement of these effects by microsomal enzyme induction. The anaesthetic agents studied included methoxyflurane, halothane, ethrane, chloroform and fluroxene. While exposure of rats to methoxyflurane, helothane and ethrane produced no significant changes in hepatic glutathione levels, or in liver histology, exposure to chloroform and fluroxene produced marked depression of liver glutathione, especially after microsomal enzyme induction. Furthermore, rats exposed to thses agents after enzyme induction developed gross centrilobular necrosis and died. It is suggested that the study of the effects of any new anaesthetic agent on liver glutathione levels could be a valuable screening test of its hepatotoxic potential, before its clinical trial.

Anesthetics↗
PubMed1983

7 alpha-Dehydroxylation of bile acids by resting cells of an unidentified, gram-positive, nonsporeforming anaerobic bacterium.

Transformation of bile acids by washed whole cells of strain HD-17, an unidentified gram-positive anaerobic bacterium isolated from human feces, was studied. 7 alpha-Dehydroxylase was produced only during adaptive growth on medium containing 7 alpha-hydroxy bile acids. Both the extent of hydroxylation and the state of conjugation of the bile acids had marked effects on the induction of the enzyme, and the order of the enzyme induction was conjugated cholic acid much greater than cholic acid greater than taurochenodeoxycholic acid greater than or equal to chenodeoxycholic acid. The addition of excess glucose to the growth medium appreciably reduced the enzyme level. The induced enzyme required strict anaerobic conditions for activity and had an optimal pH range of 6.5 to 7.5. In contrast with the induction of the enzyme, the induced enzyme showed a low degree of substrate specificity between cholic acid and chenodeoxycholic acid, with some preference for the former. In addition, the organism contained 3 alpha-, 7 alpha-, and 12 alpha-hydroxysteroid dehydrogenases, and the addition of bile acids to the medium somewhat enhanced the production of the oxidoreductases. The dehydrogenations were obviously stimulated by oxygen as a terminal electron acceptor. The organism also contained bile salt hydrolase.

Aerobiosis↗
PubMedDate not supplied

[Role of histamine as an intermediary in the action of estradiol on the rat uterus: inhibition of the hormonal induction of enzymes using histamine antagonists].

The administration of methiamide, a blocker of histamine H2-receptors, to rats was shown to prevent the induction of hexokinase (HK) and glucose-6-phosphate dehydrogenase (G-6PD) caused by both histamine and estradiol. An inhibitory effect of methiamide remained stable up to 16 h after histamine and estradiol administration. Diphenhydramine, a blocker of histamine H1-receptors, produces a short-term inhibitory effect on the HK and G-6PD activity stimulated by histamine and estradiol. The short-term nature of the diphenhydramine effect may be attributed to a low affinity to histamine H2-receptors and histamine fast dissociation. It may be concluded that some of the estradiol effects, particularly the HK and G-6PD induction in the uterus are histamine-mediated, apparently by means of H2-receptors. The administration of histamine to rats increases the uterus mass causing its inundation, and H1- and H2-blockers prevent this effect of histamine. However, the above histamine antagonists do not inhibit uterus inundation caused by estradiol. A conclusion is made that estradiol stimulates the uterus inundation not only by means of histamine but also by some other means.

Animals↗
PubMed2003

Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease.

BACKGROUND: The cytochrome p450 (CYP) oxidative enzyme system, located primarily in the liver and small intestine, is responsible for metabolism and detoxification of numerous endogenous and exogenous substances. The most abundant CYP enzyme, CYP3A, is known to be involved in the metabolism of more than 200 commonly used medications. In experimental models of renal failure, both hepatic function and CYP enzyme content are reduced; however, direct evidence in humans is lacking. Evaluation of drug metabolism in patients with end-stage renal disease is important because these patients use a large number of medications and are at risk of adverse reactions and drug-drug interactions. METHODS: We measured hepatic CYP3A activity at baseline and after rifampin (INN, rifampicin) enzyme induction in 12 patients with end-stage renal disease and 12 healthy, age-matched controls. Hepatic CYP3A phenotype was characterized with the erythromycin breath test, and enzyme induction capacity was evaluated with a short course of rifampin (600 mg/d for 6 days). RESULTS: The end-stage renal disease group had 28% lower baseline erythromycin breath test values than controls (P <.05); however, enzyme induction capacity after rifampin administration was similar between groups (P =.70). CONCLUSION: The findings suggested that one mechanism by which patients with end-stage renal disease are at increased risk of drug toxicity is reduced activity of the CYP3A enzyme pathway.

Adult↗
PubMed2002

Safety evaluation and drug development based on biological fate of drugs -efforts made to overcome drug interaction in drug development-.

1. Assay methods to detect drug interaction in toxicological samples were established by determining cytochrome P450 content and its activity in liver samples. The O-dealkylation reaction of 7-alkoxycoumarin was indicated to reflect changes in the molecular forms of P450s, and the enzyme induction or inhibition in the toxicological samples was easily detected by using the established methods. 2. During toxicological studies of 450191-S or the sleep inducer rilmazafone, a phenobarbital type-induction of hepatic drug metabolizing enzymes was observed in animals, and the doses required for the induction differed markedly between rats and dogs. Enzyme induction was caused by some specific metabolites of 450191-S, and the plasma concentrations of these metabolites were comparable when the enzyme induction was developed in both animals. 3. A nonsteroidal antiinflammatory compound 480156-S showed a slight or no effect on microsomal drug metabolizing activity in rats. On the other hand, repeated administration of this compound to humans resulted in a marked decrease in the oxidative metabolism of 480156-S, followed by a marked increase in the plasma concentrations of the compound. When volunteers were given 480156-S followed by several drugs, such as tolubutamide, the plasma clearance was delayed remarkably, indicating a severe drug interaction. 4. Cytochrome P450 belonging to the CYP2C family was indicated to participate in the oxidative metabolism of 480156-S in both rat and human liver microsomes. The preincubation of microsomes with 480156-S caused a concentration-dependent inhibition of CYP2C-dependent tolubutamide hydroxylation reaction in both rats and humans. There was a marked species difference in the susceptibility to the inhibitory effect of 480156-S, and the concentration required to inhibit rat CYP2C was almost 10 times higher than that required in humans. 5. The cephem antibiotics having N-methyltetrazolethiol (NMTT) at the 3'-position substituent were demonstrated to inhibit mitochondrial low K(m) aldehyde dehydrogenase (ALDH), and produced disulfiram-like (Antabuse) reaction during alcohol metabolism. Pharmacokinetic studies indicated that NMTT released from the antibiotics in bile duct or intestine cause the inhibitory action followed by the development of disulfiram-like reaction. 6. Attempts had been made to develop new cephem antibiotics lacking the disulfiram-like reaction by changing the chemical structure of 3'-position substituents, and a hydroxyethyltetrazolethiol was found not to inhibit the enzyme. Based on this result, together with the antibacterial activity, we have developed a new oxacephem antibiotic flomoxef (6315-S). Flomoxef showed no disulfiram-like reaction both in rats and human.

Journal Article↗
PubMed1983

Induction of spermidine N1-acetyltransferase by sodium n-butyrate and phytohemagglutinin in bovine lymphocytes.

An increased activity of spermidine N1-acetyltransferase was induced in bovine lymphocytes by stimulation with either sodium n-butyrate or phytohemagglutinin (PHA). The acetylase activity was elevated by 2- to 3-fold 24 h after the addition of butyrate, whereas a similar increase of the enzyme activity was found 48 h after stimulation with PHA. When butyrate and PHA were added to the lymphocyte suspensions simultaneously, the peak of enzyme induction was observed at 24 h after the addition and the increase (9-fold) was found to be more than additive. Since the increases in acetylase activity by both butyrate and PHA were markedly inhibited by actinomycin D or cycloheximide, they appear to have resulted from the synthesis of new protein rather than the release of the enzyme from a cryptic inactive form. The enzyme induced by the two agents was most active with spermidine as a substrate, but spermine was also acetylated to a smaller extent (25% of spermidine). Virtually no acetylation was observed with putrescine. Also, the product formed from spermidine and acetyl CoA was more than 90% N1-acetylspermidine. These results indicate that the acetylases induced by the two agents are similar. Although the addition of indomethacin or 8-bromocyclic AMP to PHA-stimulated lymphocytes caused an inhibition of the enzyme induction, no such inhibitory effect was found in the case of enzyme induction by butyrate. These results indicate that both sodium n-butyrate and PHA induce spermidine N1-acetyltransferase in bovine lymphocytes, but the induction mechanisms are different from each other.

Acetyltransferases↗