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PubMed2000

Effects of prenylated flavonoids and biflavonoids on lipopolysaccharide-induced nitric oxide production from the mouse macrophage cell line RAW 264.7.

Certain flavonoid derivatives possess anti-inflammatory activity in vitro and in vivo. Besides their antioxidative properties and effects on the arachidonic acid metabolism including cyclooxygenase/lipoxygenase inhibition, some flavones and flavonols were previously found to show inhibitory activity on nitric oxide production by inducible nitric oxide synthase (iNOS; NOS type 2) through suppression of iNOS induction. As part of our continuing investigations, the effects of unique and minor flavonoids (prenylated flavonoids and biflavonoids) on nitric oxide production from lipopolysaccharide-induced macrophage cell line (RAW 264.7) were evaluated in order to establish their inhibitory activity on NO production and correlate this action with their in vivo anti-inflammatory potential. Among the derivatives tested, prenylated compounds including morusin, kuwanon C, and sanggenon D and biflavonoids such as bilobetin and ginkgetin were found to inhibit NO production from lipopolysaccharide (LPS)-induced RAW 264.7 cells at > 10 microM. Inhibition of nitric oxide production was mediated by suppression of iNOS enzyme induction but not by direct inhibition of iNOS enzyme activity. An exception was echinoisoflavanone that inhibited iNOS enzyme activity (IC50 = 83 microM) and suppressed iNOS enzyme induction as well. While most prenylated derivatives showed cytotoxicity to RAW cells at 10-100 microM, all biflavonoids tested were not cytotoxic. Since nitric oxide (NO) produced by inducible NO synthase (iNOS) plays an important role in inflammatory disorders, inhibition of NO production by these flavonoids may contribute, at least in part, to their anti-inflammatory and immunoregulating potential in vivo.

Animals↗
PubMed1984

Effect of aging on changes in substrate and effector levels of rat-liver glycolytic and lipogenic enzymes during induction.

When 1-, 2- and 9-month-old rats adapted to a stock diet were fed a fat-free/high-sucrose diet, the changes in the substrate and effector levels of glycolytic and lipogenic enzymes in liver, and the effects of aging on the changes were investigated. By the sucrose diet feeding, the activities of phosphofructokinase, pyruvate kinase and fructokinase were increased, whereas hexokinase activity was markedly decreased. The fructose 1-phosphate levels were significantly increased in the liver, while conversely, the glucose 6-phosphate and fructose 6-phosphate levels were decreased. As a result of sucrose diet feeding, the changed enzyme activities would appear to be consistent with the metabolic pathway for fructose being predominant over that for glucose. Consequently, the concentrations of acetyl-CoA, citrate and malate were increased and would in turn appear to favour an increase in lipogenesis. The changes in the substrate and effector levels of lipogenic enzymes were reduced with aging, as were those in the enzyme activities. However, the changes in enzyme activities and metabolite levels of glycolysis were not much affected with aging.

Acetyl-CoA Carboxylase↗
PubMed2006

Influence of dimethyl sulfoxide on extracellular enzyme production by Pleurotus ostreatus.

Dimethyl sulfoxide (DMSO) is commonly used as a co-solvent to dissolve poorly water-soluble biologically active agents to assess their biological activities such as for enzyme induction. The question addressed was whether DMSO can be assumed to be an inert co-solvent. The influence of DMSO on the production of extracellular enzymes by Pleurotus ostreatus was investigated. DMSO functioned as either an inducer or a repressor, depending on the enzyme studied. The production of laccase and endo-1,4-beta-xylanase increased by 29 and 250%, respectively, in presence of DMSO. However, DMSO repressed the activities of manganese peroxidase, beta-glucosidase, beta-xylanase, and endo-1,4-beta-glucanase by 30, 33, 99 and 16%, respectively. These results raise concerns about the interpretation of bioactivity measurements when DMSO is assumed to function as an inert co-solvent to solubilize water-insoluble molecules.

Biotechnology↗
PubMed1992

Dose-response relationships of hepatic acyl-CoA oxidase and catalase activity and liver mitogenesis induced by the peroxisome proliferator ciprofibrate in C57BL/6N and BALB/c mice.

The dose-response for key hepatic effects of the peroxisome proliferator ciprofibrate, 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2- methylpropanoic acid, was delineated in mice and strain differences in response were demonstrated. Ciprofibrate was fed at concentrations ranging from 0.1 to 250 ppm to male C57BL/6N and BALB/c mice and the induction of hepatic acyl-CoA oxidase and catalase, peroxisomal enzymes involved in the formation and degradation of hydrogen peroxide, and liver hepatomegaly and mitogenesis were measured. No effect was found for enzyme induction at 5.0 ppm or less in either strain. Likewise, hepatomegaly was not found at 5.0 ppm, but mitogenesis was observed in BALB/c mice at 1.0 ppm. C57BL/6N mice demonstrated greater basal and postexposure acyl-CoA oxidase activity than BALB/c mice, while BALB/c mice demonstrated greater catalase activity and induction of liver mitogenesis. The threshold exposure level for induction of acyl-CoA oxidase activity was approximately the same as that for induction of mitogenesis in C57BL/6N mice; in contrast, the threshold exposure level for induction of acyl-CoA oxidase activity was at least one order of magnitude greater than that required for induction of mitogenesis in BALB/c mice. Thus, the induction of the peroxisomal enzyme involved in the formation of hydrogen peroxide and increased mitogenesis are not mechanistically linked. The differential effects observed in the two mouse strains provide the basis for development of a quantitative model of peroxisome proliferator-induced carcinogenicity in which cellular effects can be related to carcinogenicity.

Acyl-CoA Oxidase↗
PubMed1991

Characterization of human spermidine/spermine N1-acetyltransferase purified from cultured melanoma cells.

Extreme inducibility of spermidine/spermine acetyltransferase (SSAT) by bis-ethyl derivatives of spermine in human large cell lung carcinoma and melanoma cells has prompted biochemical characterization of the purified enzyme. Treatment of human MALME-3 melanoma cells with 10 microM N1,N11-bis(ethyl)norspermine (BENSPM) for 48-72 h increased SSAT activity by some 1000- to 4000-fold and enabled purification of the enzyme by established procedures--binding on immobilized spermine and elution with spermine followed by binding on Matrex Blue A and elution with coenzyme A. The enzyme showed a single band by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a single subunit species and molecular weight of approximately 20,300 Da. By gel permeation chromatography, the holoenzyme was found to have a molecular weight of 80,000 Da, suggesting a total of four identical subunits. Purified SSAT had a specific activity of 285 mumol/min/mg for spermidine and Km values of 5.9 microM for acetylcoenzyme A, 55 microM for spermidine, 5 microM for spermine, 36 microM for N1-acetylspermine, 1.6 microM for norspermidine, and 4 microM for norspermine. Homologs of BENSPM were found to be competitive inhibitors of spermidine acetylation, with Ki values of 0.8 microM for BENSPM, 1.9 microM for N1,N12-bis-(ethyl)spermine and 17 microM for N1,N14-bis-(ethyl)-homospermine. Correlation of these values with the relative abilities of the homologs to increase SSAT in intact cells suggests that formation of an enzyme inhibitor complex may play a contributing role in enzyme induction.

Acetyltransferases↗
PubMed1978

Pesticide-induced changes in hepatic microsomal enzyme systems: further studies on the effects of 1,1,-di(p-chlorophenyl)-2-chloroethylene (DDMU) in the Japanese quail.

Changes in the liver resulting from the low level dietary administration of 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU),p,p'-DDT, o,p'-DDT, p,p'-DDD and p,p'-DDE to Japanese Quail have been monitored. DDMU was exceptional in causing substantial increases in relative liver wt. and hepatic glucose-6-phosphatase after feeding at 100 ppm for 28 days. The time course of liver enzyme induction by DDMU has also been studied in Japanese Quail after periods of dietary administration ranging from 1--28 days with particular reference to changes in hepatic cytochrome P-450 and relative liver wt. Structural changes in the liver have been followed by reference to protein and lipid components. The hepatic response to DDMU appears to be biphasic. Initially there are substantial increases in hepatic cytochrome P-450 and relative liver wt., but the latter is largely due to accumulation of triglycerides. After approximately 20 days the level of hepatic cytochrome P-450 remain at a high 'plateau' level. This secondary phase of liver induction probably involves cell proliferation. It is concluded that DDMU causes major changes in the avian liver and either directly or through a metabolite causes pronounced microsomal enzyme induction.

Animals↗
PubMed1983

Induced tolerance to acrylonitrile toxicity by prior acrylonitrile exposure.

Pretreatment by inhalation with sublethal concentrations of acrylonitrile protects rats from subsequent, normally lethal, ACN exposures. However, inhalation-induced tolerance to ACN does not protect against subsequent poisoning by cyanide. Metabolic liberation of cyanide has been suggested to be responsible for the toxicity of ACN. Protection against ACN toxicity is not provided by pretreatment with compounds which have structural similarity to ACN, i.e. acrylamide or ethylene, nor by cyanide per se. Enzyme induction with Aroclor 1254 also does not protect against ACN toxicity. The latter data suggest that the tolerance resulting from ACN pretreatment is not the result of enzyme induction and the basis for the protective effect of ACN inhalation pretreatment remains unclear.

Acrylonitrile↗
PubMed2006

Hyperforin in St. John's wort drug interactions.

Recently, interactions of herbal medicines with synthetic drugs came into focus of particular interest. In the past 3 years, more than 50 papers were published regarding interactions between St. John's wort (Hypericum perforatum L.; SJW) and prescription drugs. Co-medication with SJW resulted in decreased plasma concentrations of a number of drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphane, simvastatin, and oral contraceptives. Sufficient evidence from interaction studies and case reports indicate that SJW is a potent inducer of cytochrome P450 enzymes (particularly CYP3A4) and/or P-glycoprotein. Recent studies could show that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product. Products that do not contain substantial amounts of hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction. On the other hand, some evidence suggests that hyperforin may also contribute to the antidepressant activity of SJW. However, clinical studies using SJW preparations with a low hyperforin amount (<1%) clearly demonstrated the superiority of this plant extract over placebo and its equivalence to imipramine and fluoxetine in the treatment of mild to moderate forms of depression. In the present paper clinical significant SJW interactions are critically evaluated against the background of hyperforin.

Bridged Bicyclo Compounds↗
PubMed2000

[Antiepileptic drugs and the liver].

OBJECTIVES: We review the metabolism of antiepileptic drugs with particular emphasis on the formation of active metabolites and toxic intermediate metabolites, together with the factors altering this and the possibility of interactions between the antiepileptic drugs themselves and with other drugs. DEVELOPMENT: Most antiepileptic drugs undergo complex metabolic processes in the liver which determine the time course of their concentration in the organism and therefore their therapeutic and toxic effects. Also, the processes by which drugs are metabolised may be influenced by many physiological and pathological factors, as well as the presence of other drugs which cause clinically relevant interactions. We analyze the function of the liver in the metabolism of these drugs with special reference to the microsome oxidation mediated by cytochrome P-450 and the glucuronidation catalysed by glucuronosyltransferase and the processes of enzyme induction and inhibition. Subsequently, we describe the metabolism of the antiepileptic drugs, their main routes of elimination, factors affecting this, role of the active and intermediate metabolites and the involvement of the enzyme induction and inhibition underlying the interactions of these drugs. Finally, we describe the metabolism of the most important classical and new antiepileptic drugs, the isoforms of cytochrome P-450 involved, the factors altering this and the most relevant interactions with other antiepileptic and non-antiepileptic drugs. CONCLUSION: Knowledge of the paths by which the antiepileptic drugs are metabolised, particularly the isoforms of cytochrome P-450 involved facilitates understanding of the influence of various factors on the metabolism of drugs, and also of their complex interactions.

Anticonvulsants↗
PubMed1987

[6 beta-hydroxycortisol: a non-invasive reflection of enzymes of drug metabolism].

6-beta-hydroxycortisol (6-beta-OHF) is the main unconjugated metabolite of cortisol in human urine. 6-beta-OHF could be assayed in urine by several methods : chromatography followed by colour reaction, high performance liquid chromatography, radioimmunoassay and enzyme immunoassay. Urinary 6-beta-OHF is increased in some physiological conditions (such as pregnancy) and pathological states (such as hypercortisolemia and liver disease). The measurement of 6-beta-OHF in human urine may provide a useful index of enzyme induction, its excretion being enhanced by many inducers of the mixed function oxygenase.

Enzyme Induction↗
PubMed1997

Regulation of DNA metabolic enzymes upon induction of preB cell development and V(D)J recombination: up-regulation of DNA polymerase delta.

Withdrawal of interleukin-7 from cultured murine preB lymphocytes induces cell differentiation including V(D)J immunoglobulin gene rearrangements and cell cycle arrest. Advanced steps of the V(D)J recombination reaction involve processing of coding ends by several largely unidentified DNA metabolic enzymes. We have analyzed expression and activity of DNA polymerases alpha, beta, delta and epsilon, proliferating cell nuclear antigen (PCNA), topoisomerases I and II, terminal deoxynucleotidyl transferase (TdT) and DNA ligases I, III and IV upon induction of preB cell differentiation. Despite the immediate arrest of cell proliferation, DNA polymerase delta protein levels remained unchanged for approximately 2 days and its activity was up-regulated several-fold, while PCNA was continuously present. Activity of DNA polymerases alpha,beta and epsilon decreased. Expression and activity of DNA ligase I were drastically reduced, while those of DNA ligases III and IV remained virtually constant. No changes in DNA topoisomerases I or II expression and activity occurred and TdT expression was moderately increased early after induction. Our results render DNA polymerase delta a likely candidate acting in DNA synthesis related to V(D)J recombination in lymphocytes.

Animals↗
PubMed1989

In vitro accumulation of thyroid hormones by cultured rat hepatocytes and the biliary excretion of iodothyronines in rats treated with a novel histamine H2-receptor antagonist.

The administration of SK&F 93479, a novel histamine H2 antagonist, to Wistar rats has been shown to produce thyroid lesions associated with an increased clearance of plasma thyroxine (T4) and elevated plasma TSH concentrations. To determine if these changes were mediated via an increase in the hepatic clearance of thyroid hormones, the biliary clearance and hepatic accumulation of iodothyronines were measured in rats and cultured hepatocytes treated with SK&F 93479. Both the in vitro and in vivo results showed that treatment with SK&F 93479 caused an increased hepatic accumulation (approx. 200% of control) and biliary excretion (2-3-fold control values) of T4 but had little or no effect on T3 uptake. The in vitro studies showed that the treatment related increase in hepatic thyroxine accumulation was temperature and therefore probably energy dependent, while inhibition of cytochrome P-450 dependent enzyme activity did not alter the accumulation of T4 suggesting that the parent compound and not some oxidative metabolite was responsible for the hepatic effects. Chromatographic analysis of bile from SK&F 93479 and phenobarbitone-treated rats showed that in the latter animals 81% of the T4 was present as the glucuronide conjugate (consistent with enzyme induction) whereas in the SK&F 93479-treated rats only 25% was present as the conjugate with 75% being in the unconjugated form. These studies show that SK&F 93479 increases the hepatic accumulation and biliary clearance of T4 by a novel mechanism not associated with liver microsomal enzyme induction.

Animals↗
PubMed2003

Effect of cytochrome P-450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female mice.

The studies presented were designed to investigate the effects of cytochrome P450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female B6C3F(1) mice. Groups of female B6C3F(1) mice were exposed to dynamic atmospheres containing tetrahydrofuran (THF) concentrations of 0, 5,400 or 15,000 mg/m(3) for 6 h per day, for 5 consecutive days. One-half of the animals in each THF exposure group were pretreated with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) at 100 mg/kg (i.p.) 1 h before the start of each THF exposure period. Treatment with THF at 15,000 mg/m(3) caused marked microsomal enzyme induction in the liver. The cytochrome P450 content was nearly doubled (+98%), pentoxyresorufin-O-depentylase (PROD) and ethoxyresorufin-O-deethylase (EROD) activities were increased by 600% and 160%, respectively. ABT pretreatment effectively blocked microsomal enzyme induction at 15,000 mg/m(3). THF exposure had no effect on the subcellular morphology of hepatocytes, whereas ABT-pretreatment caused centrilobular fatty change. THF at 15,000 mg/m(3) caused increased cell proliferation in zone 3 (central vein region) of the liver (according to Rappaport), as indicated by a significantly higher PCNA (Proliferating Cell Nuclear Antigen) labelling index, but there were no effects at 5,400 ppm. ABT pretreatment prior to THF exposure at 15,000 mg/m(3) caused an exacerbated proliferative response of mouse liver, significantly higher PCNA labelling indices being observed in zones 2 (midzonal region) and 3. The exacerbated proliferative response of mouse liver under conditions of inhibited THF metabolism suggests that the mitogenic effects are related to prevailing THF tissue concentrations and not to the generation of THF oxidative metabolite(s).

Administration, Inhalation↗
PubMed1991

The effect of environmental factors on the pharmacokinetic behaviour of organic solvent vapours.

A review of the literature concerning environmental factors affecting toxicokinetic behaviour of organic solvents revealed that alcohol consumption and exposure to other organic solvents are of great importance among such factors. An insight into how environmental factors affect the toxicokinetic behaviour of organic solvents is discussed by modelling (a) the effect of alcohol consumption on the toxicokinetics of trichloroethylene (TRI), and (b) the effect of the metabolic interaction between benzene and toluene. In general, hepatic metabolism of an organic solvent (substrate) is assumed to follow the Michaelis-Menten equation, v = Vmax.S/(Km + S), where v is the rate of substrate metabolism, Vmax and Km the maximum velocity and Michaelis constant for the metabolism, respectively, and S the substrate concentration in the liver. On the assumption of competitive inhibition, inhibition of the substrate metabolism by the simultaneous presence of ethanol or other organic solvents (inhibitors) can be expressed as follows: v = Vmax.S/[Km + (Km/Ki)I + S] where I is the inhibitor concentration in the liver and Ki the inhibitor constant toward the substrate metabolism. An increase in Vmax without a change in Km can represent enzyme induction due to alcohol consumption or previous repetitive exposure to other solvents. A simulation study on the effect of alcohol consumption on the metabolism of TRI revealed that the lower the exposure concentration, the larger the inhibitory effect of ethanol. In contrast, the effect of enzyme induction following alcohol consumption makes its full appearance only when the exposure concentration is high. Another simulation study on the mutual metabolic interaction between benzene and toluene suggested that at low exposure concentrations of both benzene and toluene where enzymes are supposed to have in reserve some capacity to catalyse the metabolism of both solvents, each solvent inhibits only slightly the metabolism of the other. On the other hand, at high exposure concentrations where enzymes have little or no capacity in reserve, the simultaneous presence of benzene and toluene notably suppresses the metabolism of each other.

Alcohol Drinking↗
PubMed2005

Selective glucocorticoid receptor nonsteroidal ligands completely antagonize the dexamethasone mediated induction of enzymes involved in gluconeogenesis and glutamine metabolism.

Glucocorticoids (GCs) are vital multi-faceted hormones with recognized effects on carbohydrate, protein and lipid metabolism. Previous studies with the steroid antagonist, RU486 have underscored the essential role of GCs in the regulation of these metabolic pathways. This article describes the discovery and characterization of novel GRalpha selective nonsteroidal antagonists (NSGCAs). NSGCAs 2 and 3 are spirocyclic dihydropyridine derivatives that selectively bind the GRalpha with IC(50s) of 2 and 1.5 nM, respectively. Importantly, these compounds are full antagonists of the induction by dexamethasone (Dex) of marker genes for glucose and glutamine metabolism; the tyrosine amino transferase (TAT) and glutamine synthetase (GS) enzymes, respectively. In contrast, GC-dependent transcriptional repression of the collagenase 1 (MMP-1) enzyme, an established GRalpha responsive proinflammatory gene; is poorly antagonized by these compounds. These NSGCAs might have useful applications as tools in metabolic research and drug discovery.

Animals↗
PubMed1988

[Hepatic mono-oxygenases].

Most drugs and xenobiotics are lipid-soluble compounds that need to be transformed into more polar water-soluble molecules by a system of hepatic monoxygenases in order to be excreted by the kidney and the liver. This system is also called cytochrome P-450. It is found in animals, as well as plants. It is located in the cellular endoplasmic reticulum of numerous tissues, but it is most active in the liver. It is made up of several isoenzymes differing from one another by the structure of their apoproteins, their immunological characteristics and their affinity for various substrates. Cytochrome P-450 has great variability, being influenced by exogenous factors (drug intake, ionizing radiation, stress, diet) and individual endogenous factors (age, sex, genetic factors). Several non specific tests exploring the system are available. They include: direct investigations carried out on liver biopsies, which are seldom used in clinical practice, and indirect investigations, such as the measurement of the clearance of exogenous substances, of urinary metabolites of endogenous substances and of specific enzymes. Induction and inhibition of microsomal activity are of the utmost interest to the clinician in various fields such as toxicology, carcinogenesis, drug interactions or drug habituation, metabolic regulations and maintenance of body homeostasis. Seven classes of enzyme inducers have been defined, but the exact mechanism of this has only been identified for two of them (the barbiturate and polycyclic hydrocarbon groups). Several drugs have been identified as enzyme inhibitors, the best known to the anaesthesiologist being macrolide antibiotics, imidazole derivatives, cimetidine, chloramphenicol and isonazide.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoglycosides↗
PubMed1989

Clofibrate induces carnitine acyltransferases in periportal and perivenous zones of rat liver and does not disturb the acinar zonation of gluconeogenesis.

Clofibrate induces hypertrophy and hyperplasia and marked changes in the activities of various enzymes in rat liver. We examined the effects of treatment of rats with clofibrate on enzyme induction and on rates of metabolic flux in hepatocytes isolated from the periportal and perivenous zones of the liver. Clofibrate induced the activities of carnitine acetyltransferase (90-fold), carnitine palmitoyltransferase (3-fold) and NADP-linked malic enzyme (3-fold) to the same level in periportal as in perivenous hepatocytes, suggesting that these enzymes were induced uniformly throughout the liver acinus. Increased rates of palmitate metabolism and ketogenesis after clofibrate treatment were associated with: a more oxidised mitochondrial redox state; diminished responsiveness to glucagon and loss of periportal/perivenous zonation. Despite the marked liver enlargement and hyperplasia caused by clofibrate, the normal periportal/perivenous zonation of alanine aminotransferase and gluconeogenesis was preserved in livers of clofibrate-treated rats, indicating that clofibrate-induced hyperplasia does not disrupt the normal acinar zonation of these metabolic functions.

Acyltransferases↗
PubMed1994

A comparative study of serum F protein and other liver function tests as an index of hepatocellular damage in epileptic patients.

Gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP) may not be sensitive indicators of hepatocellular damage in patients taking anticonvulsant drugs as raised levels may only reflect enzyme induction. Aspartate aminotransferase (AST) is a specific, but relatively insensitive marker of liver damage and has a poor correlation with liver histology. Serum F protein is found in high concentration in the liver and levels are not influenced by enzyme induction. We measured serum F protein levels in patients taking carbamazepine (CBZ) and phenytoin (PHT) as monotherapy and in patients receiving multiple drugs. We compared the results with patients taking sodium valproate (VPA). Serum F protein levels were elevated in 6%, 22% and 13% of patients receiving CBZ, PHT and VPA, respectively. Raised GGT levels were reported for both the CBZ (26%) and PHT (78%) groups. Raised ALP levels were observed in 16%, 25% and 4% of the CBZ, PHT and VPA groups, respectively. Raised levels of serum F protein in the VPA group and the absence of any associated increases in either GGT or AST may further support the suggestion that serum F protein is an indicator of hepatocellular dysfunction associated with anticonvulsant therapy. However, further correlation with liver histology is required.

Adult↗