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PubMed1987

Studies on biomodulators of glucocorticoid actions; the nature and the modes of actions of glucocorticoid potency amplifiers.

We have found many compounds that amplify the action of glucocorticoid without themselves having any glucocorticoid-like action and have proposed the concept of 'Glucocorticoid Action Biomodulators'. These biomodulators consist of 'Glucorticoid Sensitivity Amplifiers', which greatly amplify the action of glucocorticoid at doses of glucocorticoid that alone have minimal effects, and 'Glucocorticoid Potency Amplifiers', which markedly enhance the effect of glucocorticoid at doses that have maximal effects. Potent activators of protein kinase C, such as 1,2-racemic dioctanoylglycerol, 12-o-tetradecanoyl-phorbol-13-acetate, and epidermal growth factor (EGF), markedly enhanced the induction of tyrosine aminotransferase and ornithine decarboxylase by dexamethasone in adrenalectomized rats in vivo and in primary cultures of adult rat hepatocytes in vitro. They amplified enzyme induction by even a large amount of dexamethasone that had a maximal effect, but had no effect in the absence of glucocorticoid. These modes of amplification show that these compounds are 'Glucocorticoid Potency Amplifiers'. They amplified not only enzyme induction in liver but also growth inhibition by glucocorticoid of solid tumor L5178Y lymphoblasts. They specifically amplified the actions of glucocorticoids and did not amplify the actions of other steroids, such as 17-beta estradiol, glucagon and insulin. The induction of tyrosine aminotransferase by glucocorticoid and its amplification by EGF were both inhibited by 1-(5-iso-quinoline-sulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, and not by N-[2-(methylamino)-ethyl]-5-isoquinoline-sulfonamide, an inhibitor of cyclic nucleotide dependent protein kinases, suggesting that the induction and the amplification are mediated by protein kinase C.

Animals↗
PubMed1986

Substituted polychlorinated dibenzofuran receptor binding affinities and aryl hydrocarbon hydroxylase induction potencies--a QSAR analysis.

The rat hepatic cytosolic receptor binding affinities of 8-substituted 2,3-dichlorodibenzofurans and 8-substituted 2,3,4-trichlorodibenzofurans have been measured. The EC50-value for each compound was determined by dose-response competitive displacement of 2,3,7,8-[3H] tetrachlorodibenzo-p-dioxin (TCDD). Multiple parameter linear regression analysis of the data using several substituent parameters [lipophilicity (pi), hydrogen bonding (HB), electronegativity (sigma op), STERIMOL (delta B5)] demonstrated that for both sets of ligands, the binding affinities were dependent on substituent pi-values. The equations derived for the 8-substituted 2,3,4-trichlorodibenzofurans (a) and 8-substituted 2,3-dichlorodibenzofurans (b) were (Formula: see text) remarkably similar, moreover the relatively bulky t-butyl substituent was treated as an outlier for both calculations. The in vitro induction of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) in rat hepatoma H-4-II E cells by both sets of ligands demonstrated that there was not a rank order correlation between induction potencies and receptor binding affinities for these compounds. Analysis of the data for the 8-substituted 2,3-dichlorodibenofurans demonstrated that the monooxygenase enzyme induction was dependent on substituent lipophilicity and a STERIMOL (delta B5) factor which is related to (Formula: see text) substituent width. In contrast, the equation for the 8-substituted 2,3,4-trichlorodibenzofurans also included a substituent sigma op Hammett constant. The results indicate that although the binding affinities of the two sets of ligands are dependent only on substituent pi-values, their enzyme induction activities are both substituent and chlorine substitution pattern-dependent.

Animals↗
PubMed1977

Hepatic enzymes, their induction and usefulness in predicting maximal serum bilirubin levels in premature newborn infants.

Sixty-seven babies were utilized to (a) document the serum bilirubin lowering effect and safety of a phenobarbitone and nikethamide combination in neonatal hyperbilirubinaemia of non-hemolytic origin; (b) determine whether birthweight and/or SGOT, SGPT or SGGT activity on day one of life correlated with the maximum serum bilirubin level achieved; and (c) investigate the pattern of hepatic enzyme levels in serum under normal conditions anf following drug induction. Results indicate a significantly lower serum bilirubin level in the treated group of babies. Birthweight and day one SGGT levels, and SGGT/birthweight ratio correlated well with the maximum serum bilirubin reached, the latter ratio being particularly useful in predicting the degree of hyperbilirubinaemia.

Alanine Transaminase↗
PubMed2000

Studies on the toxic interaction between monensin and tiamulin in rats: effects on P450 activities.

Studies were carried out to investigate the effects of monensin and tiamulin, and the simultaneous administration of both compounds on microsomal enzymes in rats. In Phase I of the experiments the effects of monensin and tiamulin were studied separately (monensin 10, 30, and 50 mg/kg or tiamulin 40, 120, and 200 mg/kg body weight, respectively), while in Phase II the two compounds were administered simultaneously (monesin 10 mg/kg and tiamulin 40 mg/kg b.w., respectively). When monensin was administered by itself, it exerted no significant effect on microsomal liver enzymes. In a few cases, slight inhibition of certain enzyme activities was seen. Tiamulin provoked a dose-dependent hepatic enzyme induction. The combined administration of monensin and tiamulin at low doses (10 and 40 mg/kg, respectively) resulted in marked elevation of P450-related enzyme activities. The enzyme induction was more pronounced in females than in males. The results suggest that the simultaneous administration of tiamulin may influence the biotransformation of monensin, possibly increasing the amount of reactive metabolite(s) of the ionophore antibiotic.

Animals↗
PubMed2000

Apoptosis and cell proliferation in rat hepatocytes induced by barbiturates.

To examine the effect on cell population in hepatocytes of phenobarbital (PB) and other barbiturates, PB, allobarbital (ALB), barbital sodium (BS) and barbituric acid (BA) were given orally to male rats for 7 consecutive days. Although there was no apparent change in non-promoting BA, hepatomegaly was induced by PB, BS and ALB, which are promoters of hepatocarcinogenesis. In PB- and BS-treated livers, hepatomegaly was attributable to hepatocyte proliferation and enzyme induction. In ALB-treated liver, it was attributable to enzyme induction. The level of cell proliferation was reduced to less than the control values following withdrawal of PB, ALB and BS. It seemed that the degree of suppression of cell proliferation following withdrawal of these compounds correlated to the degree of cell proliferation (PB>BS>ALB) during treatment. In PB-treated liver, apoptosis was induced during treatment, serving to eliminate the excess of hepatocytes. This suggests that short-term administration of PB neither induced suppression of apoptosis nor disturbed homeostasis of hepatocyte populations.

Animals↗
PubMed2004

No clinically relevant CYP3A induction with the dual angiotensin-converting enzyme/neutral endopeptidase inhibitor, M100240.

M100240, an acetate thioester of MDL 100,173, is a dual angiotensin-converting enzyme/neutral endopeptidase inhibitor currently in Phase II development. M100240 and MDL 100,173 were evaluated in an in vitro cytochrome P450 human hepatocyte model for enzyme induction. Although a dose-dependent CYP3A induction was observed between 10 and 100 microM, at 1 microM-which approaches clinically relevant plasma concentrations in humans-there was no evidence of CYP3A induction. An in vitro reporter gene assay also demonstrated the CYP3A isozyme induction potential of M100240 and MDL 100,173 with an EC(50) approximately 1.5 microM. The present study evaluated the potential for CYP3A enzyme induction in healthy volunteers. In an open-label, single-sequence, replicate-design study using midazolam as a CYP3A probe in 13 healthy volunteers, we found no evidence of clinically relevant CYP3A induction after multiple-dose administration of 50 mg M100240 orally once daily for 15 days. Single and multiple doses of M100240 increased the midazolam AUC(0-24 h) about 1.6-fold compared to baseline, suggesting weak CYP3A inhibition. Concomitant administration of midazolam and M100240 was generally safe and well tolerated. Although in vitro CYP3A induction at exposures in excess of clinically relevant human plasma concentrations has been demonstrated, there is no clinical evidence of CYP3A induction with M100240 administration at proposed therapeutic doses.

Adolescent↗
PubMed1977

Pineal protein phosphorylation during serotonin N-acetyltransferase induction.

The activity of soluble protein kinase (ATP:protein phosphotransferase,EC 2.7.1.37) and pattern of nuclear protein phosphorylation was monitored in cultured rat pineal glands during the induction of serotonin N-acetyltransferase (acetyl-CoA:serotonin N-acetyltransferase;EC 2.3.1.5)by l-isoproterenol. A nuclear protein appears to be phosphorylated during the early stages of enzyme induction but is not phosphorylated at later stages of induction. This correlates well with the need for RNA synthesis associated with the induction process. The nuclear protein was also phosphorylated when the pineal glands were treated with dibutyryl 3':5'-cyclic AMP. The soluble protein kinase activity appeared to decline during mid-to-late stages of enzyme induction, but there was no concomitant increase in the particulate protein kinase activity.

Acetyltransferases↗
PubMed1979

[Deviation in cortisol metabolism induced by rifampicin. Therapeutic consequences in adrenal failure (author's transl)].

Deviation of cortisol metabolism in favour of its 6 beta-hydroxylated derivative was demonstrated in two patients with adrenal failure receiving substitution corticosteroid therapy and rifampicin. The existence of a frank increase in the metabolic clearance antipyrin was in favour of an hepatic enzyme induction. After rifampicin treatment was stopped, the 24 hour urinary excretion of 6 beta-OH-F returned to normal, demonstrating the responsability of the drug. This enzyme induction results in a need to increase the dose of hydrocortisone substitution therapy in patients with Addison's disease treated with rifampicin.

Addison Disease↗
PubMed1985

On the mechanisms of induction of cancer-protective enzymes: a unifying proposal.

Induction of detoxification enzymes is a major mechanism whereby a wide variety of chemical agents protect rodents against neoplastic, mutagenic, and other toxicities of carcinogens. The enzyme NAD(P)H:(quinone acceptor) oxidoreductase (EC 1.6.99.2) can protect against the toxicities of quinones and is a useful marker for protective enzyme induction. Quinone reductase can be induced in murine Hepa 1c1c7 hepatoma cells and 3T3 embryo fibroblasts by compounds that are chemoprotectors in vivo, including some phenolic antioxidants, azo dyes, aromatic diamines, and aminophenols. Structurally dissimilar catechols (1,2-diphenols) and hydroquinones (1,4-diphenols) induce quinone reductase in these systems, but resorcinol (1,3-diphenol) and its substituted analogues are inactive. Furthermore, only aromatic 1,2- and 1,4-diamines and aminophenols are inducers, whereas the 1,3-diamines are completely inactive. These findings suggest that the functional capacity to form quinones or quinone-diimines, rather than the precise structure, is essential for inductive activity and that the generation of the signal for enzyme induction depends upon oxidation-reduction lability. The observations that some chemoprotective compounds (e.g., azo dyes, beta-naphthoflavone) induce both cytochromes P-450 and quinone reductase, whereas others (e.g., tert-butylhydroquinone) induce only quinone reductase, can be reconciled by the fact that inducers of the first type are metabolized by P-450 enzymes to form products that are functionally similar to compounds of the second type.

Animals↗
PubMed1990

Regulation of enzymes that detoxify the electrophilic forms of chemical carcinogens.

Most chemical carcinogens require activation to reactive electrophilic forms by Phase 1 enzymes (cytochromes P-450) in order to exert their toxic and neoplastic effects. The resultant electrophiles are susceptible to metabolic conjugation and other types of detoxications by Phase 2 enzymes (glutathione transferases, NAD(P)H: quinone reductase, glucuronosyltransferases). The balance between Phase 1 and Phase 2 enzymes is an important determinant of whether exposure to carcinogens will result in toxicity and neoplasia. Measurements of the activity of quinone reductase (QR) provide an efficient method for studying the potency and mechanism of Phase 2 enzyme induction. QR can be measured easily in murine hepatoma cells (Hepa lclc7) grown in microtiter plate wells, and the inductive response of these cells closely parallels the behavior of rodent tissues in vivo. Some inducers (such as large planar aromatics) are bifunctional; they induce both Phase 1 and Phase 2 enzymes and require binding to the Ah receptor and enhanced transcription of the cytochrome P1-450 system. Other inducers (e.g., phenolic antioxidants, 1, 2-dithiole-3-thiones, coumarins, thiocarbamates) are monofunctional and are independent of Ah receptor function. Monofunctional enzyme induction protects against carcinogens. The induction of Phase 2 enzymes by monofunctional inducers depends on the presence, or acquisition by metabolism, of electrophilic centers, and many of these inducers are Michael reaction acceptors. Our search for chemoprotective enzyme inducers for potential use as chemoprotectors in man is currently focused on fumarate derivatives, as well as on the identification of other monofunctional inducers in extracts of vegetables.

Animals↗
PubMed1976

Cobalt inhibition of synthesis and induction of delta-aminolevulinate synthase in liver.

Cobalt has complex actions on the metabolism of heme in the liver. In this organ the metal potently induces heme oxygenase (EC 1.14.99.3), and decreases cellular heme and hemoprotein content. The metal also displays biphasic effects on hepatic heme synthesis. These effects are reflected in the ability of cobalt to initially inhibit synthesis of delta-aminolevulinate synthase [succinyl-CoA:glycine C-succinyltransferase (decarboxylating) EC 2.3.1.37], the rate limiting enzyme of the heme pathway, following which a later enhanced rate of formation of this enzyme occurs. In this study, cobalt was shown to block almost entirely the ability of the barbiturate analogue allylisopropylacetamide to induce delta-aminolevulinate synthase in liver. The blocking effect of cobalt on the otherwise potent enzyme inducing action of this drug was time-dependent; if the metal was injected 30 min prior to allylisopropylacetamide, inhibition of enzyme induction was complete. When the metal was administered 1.5 or more hours after allylisopropylacetamide, inhibition of enzyme induction was incomplete. Cobalt did not block the ability of the drug to directly degrade heme to "green pigment" thus the enzyme inducing action of allylisopropylacetamide and its degradative action on heme are separately mediated.

5-Aminolevulinate Synthetase↗
PubMed1986

Induction of oligo-2',5'-adenylate synthetase in human lymphoid cells treated with 5-azacytosine and 5-iododeoxyuridine.

Oligo-2',5'-adenylate synthetase activity was investigated in several human lymphoblastoid cell lines of B cell origin treated with reagents having effects on gene expression, 5-azacytosine (5AZct), 5-azacytidine (5AZcd) and 5-iodo-2'-deoxyuridine (IUdR). Enzyme activity did not increase in cells treated with 5AZcd, but the other reagents induced significant levels of activity. Interferon (IFN) activity was not detected in culture fluids of cells treated with 5AZcd or 5AZct. On the other hand, treatment of cells with IUdR led to the production of 5 to 10 units/ml IFN by NC-37 and Raji cells, but not by other human B cell lines. Enzyme induction by IUdR occurred in IFN-producing cells, NC-37 and Raji, exposed to anti-IFN-alpha sera and also in IFN-non-producing human B cells. The effect of 5AZct on enzyme induction was observed only after cultivation of cells for more than 1 month. This compound could not induce enzyme activity in Epstein-Barr virus (EBV)-negative cells, BJAB, but only in the EBV-positive cell lines NC-37 and Raji. In contrast, treatment of cells with IUdR for only 3 days induced the enzyme in all human lymphoblastoid cell lines of B cell origin except P3HR-1, but not in other human cell lines, FL, HeLa and K562. Oligo-2',5'-adenylate synthetase activity in P3HR-1 cells, which produce EBV particles, was hardly affected by IUdR or IFN treatment.

2',5'-Oligoadenylate Synthetase↗
PubMed2001

Morphology and cytochrome P450 isoforms expression in precision-cut rat liver slices.

Precision-cut liver slices are a widely accepted in vitro system for the examination of drug metabolism, enzyme induction, or hepatotoxic effects of xenobiotics. The maintenance of the distinct lobular expression and induction pattern of phase I biotransformation enzymes, however, has not been examined systematically so far. Thus, in the present study, both longitudinal and transversal sections of male rat liver slices were investigated morphologically, as well as immunohistochemically for the expression of different cytochrome P450 (CYP) isoforms after prolonged incubation or after exposure to typical inducers. Histopathological examinations revealed an increasing vacuolization of the periportal hepatocytes mainly in the middle of the slices from 6 h of incubation on, paralleled by a loss of glycogen in the respective cells. After 24 h, mainly in the center of the slices, necroses of cells occurred. After 48 h of incubation, typically a central band of coagulative necrosis flanked by superficial layers of viable cells was observed. Freshly prepared slices displayed a CYP subtypes expression as normal liver specimen, a very low centrilobular CYP 1A1 immunostaining, but a strong CYP 2B1 and 3A2 expression predominantly in the central and intermediate lobular zones. From 2 h on, the immunostaining for CYP 2B1 and 3A2 was to some extent reduced. After 24 h of incubation with beta-naphthoflavone, the CYP 1A1 and 2B1 expression was induced mainly in the viable cells around central veins, around some portal fields with bigger vessels and in the cell layers close to the slice surface. At the same sites, phenobarbital led to an increased CYP 2B1 and 3A2 expression and dexamethasone to an elevated CYP 3A2 immunostaining. These results show, that an in vitro induction of phase I enzymes in precision-cut liver slices can be demonstrated also immunohistochemically.

Animals↗
PubMed2001

Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells.

The protective adaptive response to electrophiles and reactive oxygen species is mediated by enhanced expression of phase II detoxifying genes, including glutathione S-transferases, through activation of antioxidant response element (ARE). The current study was designed to investigate the role of phosphatidylinositol 3-kinase (PI3-kinase)-Akt and mitogen-activated protein (MAP) kinase signaling pathways in the induction of rGSTA2 by tert-butylhydroquinone (t-BHQ). Nuclear ARE complex was activated 1 to 6 h after treatment of H4IIE cells with t-BHQ. The rGSTA2 mRNA level was elevated 6 to 24 h after t-BHQ treatment, which led to the enzyme induction. Activities of PI3-kinase and Akt were increased 10 min through 6 h after t-BHQ treatment, whereas wortmannin or LY294002, PI3-kinase inhibitors, completely abolished ARE binding activity and increases in rGSTA2 mRNA and protein. Extracellular signal-regulated kinase (ERK), p38 MAP kinase, and c-Jun N-terminal kinase (JNK) were all activated by t-BHQ. Treatment with PD98059, an ERK inhibitor, however, increased rGSTA2 mRNA and further enhanced t-BHQ-induced expression of rGSTA2. Neither SB203580 nor overexpression of JNK1 dominant negative mutant altered t-BHQ-inducible rGSTA2 expression. These results demonstrated that t-BHQ activated PI3-kinase and Akt, which was responsible for ARE-mediated rGSTA2 induction, and that ERK might negatively regulate rGSTA2 expression, whereas activation of p38 MAP kinase or of JNK by t-BHQ was not associated with the enzyme induction.

Animals↗
PubMed1993

Establishment of an antitoxoplasma state by stable expression of mouse indoleamine 2,3-dioxygenase.

Indoleamine 2,3-dioxygenase (IDO), a tryptophan-degrading enzyme, is inducible by various interferons (IFNs). IDO-mediated tryptophan degradation, but not the formation of IDO-catalyzed tryptophan metabolites, has been suggested as a mechanism for the antiparasitic action of IFN-gamma. To determine whether the IFN-gamma-induced IDO alone is sufficient for establishing the antiparasitic state, we constructed a mouse IDO expression plasmid containing a heavy metal-responsive metallothionein promoter and obtained a stable transformant (C6) by transfection of this plasmid into mouse rectal cancer (CMT-93) cells. In the presence of 100 microM ZnSO4, C6 cells yielded a high level of IDO; and after a 2-day culture period, the enzyme induction resulted in complete depletion of tryptophan from the culture medium. Under these conditions, the growth of Toxoplasma gondii in C6 cells infected with the organisms on day 3 after enzyme induction was completely blocked. In the absence of ZnSO4, however, IDO induction was negligible in C6 cells, and T. gondii continued to grow. Furthermore, in a transformant (CC10) carrying an antisense mouse IDO plasmid or in parental CMT-93 cells, IDO was not induced at all even in the presence of 100 microM ZnSO4, and T. gondii continued to grow in these cells as well. These results taken together indicate that complete depletion of tryptophan from the culture by IDO alone is sufficient to establish the antitoxoplasma state in mouse cells.

Animals↗
PubMed1980

Evaluation of nitroglycerin ointments in the rabbit.

The rate of percutaneous absorption of nitroglycerin from different ointment preparations was studied in the rabbit using an indirect method which suffices bioavailability requirements. Ointment bases of different lipophilic character were compared with a commercially available preparation. Rate of absorption was fastest from the least lipophilic base. A hypothesis is presented regarding the clinical observation that topical use of nitroglycerin may not show enzyme induction as was found in peroral use. According to this hypothesis while achieving therapeutically effective levels the rate of percutaneous absorption should be slow enough not to result in a systemic drug concentration critical to enzyme induction. One experimental preparation (A) resulted in practically identical rate of absorption as obtained with the standard preparation.

Animals↗
PubMed1996

Characterization of Ca(2+) flows essential in ornithine decarboxylase induction by L-asparagine in rat hepatoma cells using Ca(2+) flow inhibitors.

L-Asparagine stimulates bi-directional Ca(2+) flows and induces ornithine decarboxylase in Reuber H-35 hepatoma cells. Previously it has been shown that these effects are completely, but reversibly inhibited by lanthanum chloride. In this study we examined the role(s) of Ca(2+) flows using more specific Ca(2+) flow inhibitors. It was shown that ornithine decarboxylase induction was inhibited by CdCl(2) and verapamil at concentrations above 1 mu M and 100 mu M respectively, but was unaffected by as much as 300 mu M NiCl(2), 1 mM nifedipine, or 10 mu M omega-conotoxin. Enzyme induction was blocked by the Ca(2+)-ATPase pump antagonists vanadate and Compound 48/80 in a dose-dependent manner. These results, taken together with the observations that extracellular Ca(2+) is essential for enzyme induction but a substantial elevation of cytoplasmic [Ca(2+)] is not, suggest that Ca(2+) inflow independent of the receptor-activated Ca(2+) channels, and the Ca(2+)-ATPase mediated Ca(2+) out-flow, are both important factors in the action of L-asparagine.

Animals↗
PubMed1983

Synthesis of biodegradative threonine dehydratase in Escherichia coli: role of amino acids, electron acceptors, and certain intermediary metabolites.

The specific activity of inducible biodegradative threonine dehydratase (EC 4.2.1.16) in Escherichia coli K-12 increased significantly when the standard tryptone-yeast extract medium or a synthetic mixture of 18 L-amino acids was supplemented with 10 mM KNO3 or 50 mM fumarate and with 4 mM cyclic AMP. In absolute terms, almost four times as much enzyme was produced in the amino acid medium as in the tryptone-yeast extract medium. Enzyme induction in the amino acid medium was sensitive to catabolite repression by glucose, gluconate, glycerol, and pyruvate. An analysis of amino acid requirements for enzyme induction showed that a combination of only four amino acids, threonine, serine, valine, and isoleucine, produced high levels of threonine dehydratase provided that both fumarate and cyclic AMP were present. Immunochemical data revealed that the enzyme synthesized in the presence of these four amino acids was indistinguishable from that produced in the tryptone-yeast extract or the medium with 18 amino acids. We interpret these results to mean that not the amino acids themselves but some metabolites derived anaerobically in reactions involving an electron acceptor may function as putative regulatory molecule(s) in the anaerobic induction of this enzyme.

Amino Acids↗