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PubMed1981

Induction of group-1 and group-2 UDP-glucuronosyltransferase in microsomes from the livers of C57 Bl/6 mice.

In a study of multiple forms of liver microsomal UDPglucuronosyltransferase (EC 2.4.1.17) with different substrate specificities, enzyme induction was examined in inducible C57 Bl/6 mice pretreated with phenobarbital, 3-methylcholanthrene, Aroclor 1254, safrole, beta-naphthoflavone, and pregnenolone-16-alpha-carbonitrile. Phenobarbital and 3-methylcholanthrene were much more potent inducers than the other four compounds. 3-methylcholanthrene stimulated the glucuronidation of 4-nitrophenol, 4-bromophenol, and 4-chlorophenol ("group-1' substrates) more than phenobarbital, whereas phenobarbital stimulated the glucuronidation of 4-hydroxyphenobarbital, menthol, eugenol, 4-hydroxybiphenyl, morphine, 1-borneol, 4-hydroxyphenytoin, and 1,2,3,4-tetrahydro-1-naphthol ("group-2' substrates). This pattern is analogous to that previously observed in rat-liver microsomes.

Animals↗
PubMed1992

Regulation of perfluorooctanoic acid--induced peroxisomal enzyme activities and hepatocellular growth by adrenal hormones.

A wide variety of compounds, including hypolipidemic drugs, plasticizers and other industrial chemicals, have been found to cause liver enlargement and hepatic peroxisome proliferation by mechanisms that are unclear. Although thyroid and sex hormones have been shown to modulate the hepatic response to these chemicals, the role of adrenal hormones in these phenomena is not clear, and a few studies have produced conflicting data. Therefore this study was undertaken to investigate the role of adrenal hormones in hepatomegaly and peroxisomal enzyme induction caused by peroxisomal proliferators and to further delineate the interrelationship between these parameters. Because adrenalectomy alters hepatic drug metabolism, we have used the nonmetabolizable proliferator perfluorooctanoic acid. Our data show that hepatomegaly caused by perfluorooctanoic acid depends on corticosterone, the major glucocorticoid in rodents. Liver growth caused by perfluorooctanoic acid appears to be predominantly hypertrophic in nature, and DNA synthesis in response to perfluorooctanoic acid predominates in periportal regions of the liver lobule. Data also show that although induction of peroxisomal beta-oxidation by perfluorooctanoic acid is independent of adrenal hormones, induction of catalase is dependent on the presence of these hormones. This study supports the contention that induction of activities of various peroxisomal enzymes is controlled by different regulatory mechanisms.

Adrenal Cortex Hormones↗
PubMed1990

Estrogenic regulation of diamine oxidase activity in rat uterus.

Diamine oxidase activity was studied in female rat tissues during the estrous cycle and after 17 beta-estradiol administration. During the estrous cycle, uterine and hepatic enzyme activities were highest at proestrus and lowest at estrus, when estrogen plasma levels are known to be respectively high and low. The administration of 17 beta-estradiol to ovariectomized rats caused a rapid and prolonged increase in enzyme activity in uterus and only a transient increase in the liver. Such increases were prevented by cycloheximide and by actinomycin D administration. No changes were observed in renal enzyme activity during estrus or after hormone treatment. Our data suggest that estrogens regulate diamine oxidase activity in rat uterus by a mechanism of enzyme induction.

Amine Oxidase (Copper-Containing)↗
PubMed2001

Roger Yate Stanier, 1916-1982: a transcendent journey.

The Tenth International Symposium on Phototrophic Prokaryotes (Barcelona, 26-31 August 2000) was the latest in a series of conferences initiated by Roger Stanier in 1971 to create ties within the community of scientists working with cyanobacteria or green and purple bacteria. Consonant with Stanier's own work, the subjects of these conferences range broadly from systematics and ecology through genetics, biochemistry and physiology. The effort to define comprehensively the place of bacteria in the living world was the leitmotif in Stanier's work, the subject of one of his earliest papers (in 1941), and revisited for the final time in his autobiographical memoir of 1980. Salvador Luria noted that Stanier "...always pursued broad naturalistic interests along with chemical ones, deliberately emphasizing morphology and ecology side by side with biochemistry." Chronologically, Stanier's work addressed taxonomic and nutritional aspects of the cytophagas, enzyme induction and patterns of regulation of enzyme synthesis, aromatic degradative pathways, characterization of what would subsequently be called 70S bacterial ribosomes, the regulation of bacteriochlorophyll synthesis by nonsulfur purple bacteria, protection by carotenoids against photooxidative damage, the path of carbon in heterotrophy, the molecular basis of streptomycin dependence, the life cycle of Caulobacter, the taxonomy of pseudomonads, and, for the last 12 years of his life, wide-ranging studies of the cyanobacteria.

Bacteria↗
PubMed1991

Evidence for and possible mechanisms of non-genotoxic carcinogenesis in rodent liver.

Doses of chemicals which induce hepatocellular necrosis usually induce hepatic tumours if the dosing is frequent and is maintained for long periods. Such necrosis is usually evident within 48 h of the first administration. Similarly, chemicals that lead to marked proliferation of peroxisomes in the liver also usually induce hepatic tumours on pretracked regular dosing. For both of these phenomena failure to produce a certain level of effect, or to maintain it for sufficiently long periods, can result in the observation of a non-carcinogenic response. The exact dose/time requirements for carcinogenicity have not been defined and may be species/strain/sex-specific. Some chemicals induce liver enlargement and mitogenesis in the absence of overt hepatotoxic effects. The early phases of hepatomegaly are associated with mitogenic effects that can be measured as cells in S-phase within the first few days of administration. The later stages of hepatomegaly appear to be associated more with cellular hypertrophy. Both effects appear to be threshold-related. Further, sustained hepatomegaly is associated with proliferation of SER and the induction of a range of liver enzymes. These changes (mitogenesis, hepatomegaly, enzyme induction), in isolation, are less definitive indicators of carcinogenicity, but they occur for a sufficient number of liver-specific carcinogens that their role as early indicators is worthy of confirmed study. The major area of study required for all possible early markers of hepatocarcinogenicity is to establish the dose and time dependence of these changes in relation to the eventual appearance of tumours. Finally, the specificity of all these markers require evaluation by the study of appropriate non-carcinogens.

Animals↗
PubMed1976

The association between serum triglycerides and gamma glutamyl transpeptidase activity in diabetes mellitus.

A study conducted on 228 diabetic patients has shown a significant positive association between serum gamma-glutamyl transpeptidase (GGT) and triglyceride levels. Both fall with treatment, the most marked reduction occurring in patients on insulin. We suggest that the association between serum GGT and triglyceride levels and also the higher incidence of raised GGT and triglyceride levels in new diabetics may reflect hepatic microsomal enzyme induction of the rate-limiting enzymes of triglyceride synthesis. Serum GGT does not seem to correlate with hepatomegaly in diabetes mellitus.

Adolescent↗
PubMed2000

Cell biology of peroxisomes and their characteristics in aquatic organisms.

The general characteristics of peroxisomes in different organisms, including aquatic organisms such as fish, crustaceans, and mollusks, are reviewed, with special emphasis on different aspects of the organelle biogenesis and mechanistic aspects of peroxisome proliferation. Peroxisome proliferation and peroxisomal enzyme inductions elicited by xenobiotics or physiological conditions have become useful tools to study the mechanisms of peroxisome biogenesis. During peroxisome proliferation, the induction of peroxisomal proteins is heterogeneous, enzymes that show increased activity being involved in different aspects of lipid homeostasis. The process of peroxisome biogenesis is coordinately triggered by a whole array of structurally dissimilar compounds known as peroxisome proliferators, and investigating the effect of some of these compounds that commonly appear as pollutants in the environment on the peroxisomes of aquatic animals inhabiting marine and estuarine habitats seems interesting. It is also important to determine whether peroxisome proliferation in these animals is a phenomenon that might occur under normal physiological or season-related conditions and plays a metabolic or functional role. This would help set the basis for understanding the process of peroxisome biogenesis in aquatic animals.

Animals↗
PubMed1996

Purification and characterization of a prokaryotic xanthine dehydrogenase from Comamonas acidovorans.

Xanthine dehydrogenase (XDH) is induced in Comamonas acidovorans cells incubated in a limited medium with hypoxanthine as the only carbon and nitrogen source. The enzyme has been purified to homogeneity using standard techniques and characterized. It contains two subunits with M(r) values of 90 and 60 kDa. Gel filtration studies show the enzyme to have an alpha 2 beta 2 native structure. No precursor form of the enzyme is observed on Western blot analysis of cell extracts obtained at various stages of enzyme induction. Metal analysis of the purified enzyme shows 1.1 Mo, 4.0 Fe, and 3.6 phosphorus atoms per alpha beta protomer. Cofactor analysis shows the enzyme to contain a single molybdopterin mononucleotide and one FAD per alpha beta protomer. Electron spin resonance and circular dichroism spectral studies of the oxidized and reduced forms of the enzyme suggest the Fe centers to be two nonidentical [2Fe-2S] clusters. Electron spin resonance signals due to Mo(V) and neutral FAD radical are also observed in the reduced form of the enzyme. Purified enzyme preparations ranged from 70% to 100% functionality. The enzyme is irreversibly inactivated by CN- and is inhibited on incubation with allopurinol. With xanthine and NAD+ as substrates the enzyme has a specific activity of 50 units/mg, a kcat value of 120 s-1, an activity/flavin ratio of 1930, and respective Km values of 66 and 160 mM. Using 8-D-xanthine as substrate, a DV value of 1.8 is found with no change in Km. Thus, the Km and KD values of the enzyme for xanthine are equal. These data show Comamonas XDH to exhibit structural properties similar to bovine milk xanthine oxidase/dehydrogenase and to chicken liver xanthine dehydrogenase. Although the bacterial enzyme exhibits a 6-7-fold greater turnover rate than bovine or avian enzymes, the catalytic efficiencies (as measured by V/K) are similar for all three enzymes.

Animals↗
PubMed2000

Increased urinary excretion of tubular enzymes and proteins in children with epilepsy.

Cross-sectional analysis of children undergoing treatment with anti-epileptic drugs has shown an increased urinary excretion of tubular enzymes and proteins. This has usually been interpreted as a consequence of subclinical renal-tubular damage or enzyme induction. We measured excretion of tubular enzymes and proteins in 29 children who suffered from epileptic seizures and in 27 control children. Investigations were undertaken at diagnosis before the start of treatment and 3-4 months later. At diagnosis we found a slightly, but statistically significant increased excretion of N-acetyl-beta-glucosaminidase and alpha1-microglobulin. There was no significant difference between patients with an idiopathic and symptomatic aetiology of seizures or between patients with different seizure types. At the second investigation, in children treated with carbamazepine or valproate, no further increase occurred. We conclude that the increased excretion of tubular enzymes and proteins in children with epilepsy is most probably not due to a side-effect of the anti-epileptic drugs, but to a physiological alteration associated with the epilepsy itself. While the cause is unknown, the influence of serotonin metabolism is discussed.

Acetylglucosaminidase↗
PubMed1963

ESTROGEN-INDUCED 16-HYDROXYSTEROID DEHYDROGENASE ACTIVITY IN RAT KIDNEY.

The activity of an enzyme system which readily converts estriol to 16-ketoestradiol is present only in the kidneys of mature female rats and is absent in the kidneys of male rats and immature rats of either sex. The full enzyme activity occurs in kidneys of rats of either sex at any stage of maturity after administration of estradiol for 2 weeks. The time course of the appearance and disappearance of the enzyme, the absence of detectable inhibitors and activators, and evaluation of cofactor requirements suggest that this may be an example of enzyme induction by the hormone. Furthermore, the enzyme activity itself represents a metabolic pathway for estriol metabolism whose potential quantitative significance has not heretofore been recognized.

Castration↗
PubMed1984

Effect of high-protein diet on liver alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase in rats.

In tryptophan-niacin metabolism, alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) [EC 4.1.1.45] is known to play an important role by catalyzing the decarboxylation of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde, a metabolite of tryptophan which cyclizes spontaneously to form quinolinate. In this study, we investigated the effect of either dietary protein or amino acids on the activity of ACMSD in rats. When rats were fed on a high-protein diet ad libitum for several days, their liver ACMSD activity was greatly increased. Kidney ACMSD activity was also slightly elevated by a high-protein diet. Tryptophan, a precursor of the substrate of ACMSD, was not responsible for the increase of ACMSD activity caused by high-protein diet. On the contrary, insufficiency of dietary tryptophan rather elevated ACMSD activity. The increased amount of amino acids other than tryptophan in the diet resulted in the elevation of liver and kidney ACMSD activities. Although the increase of essential amino acids in the diet slightly elevated the liver ACMSD activity, the enzyme activity was enhanced markedly by feeding the diet containing both essential and nonessential amino acids in high concentrations. These results indicate that at least several amino acids, including some essential and nonessential ones, are responsible for the elevation of ACMSD activity which is induced by high-protein diet. Since liver ACMSD activity in adrenalectomized rats was also increased by feeding a high-protein diet, adrenocortical hormone was thought to be unnecessary for such enzyme induction.

Amino Acids↗
PubMed2003

The ideal pharmacokinetic properties of an antiepileptic drug: how close does levetiracetam come?

The pharmacokinetic properties of a drug are the primary deter-minant of the extent and duration of drug action, and influence susceptibility to clinically important drug interactions. Most of the older-generation antiepileptic drugs (AEDs) are far from ideal in terms of pharmacokinetics and interaction potential. For example, phenytoin, carbamazepine, and valproic acid exhibit non-linear kinetics; carbamazepine and valproic acid have relatively short half-lives; and most of these drugs cause either enzyme induction (phenytoin, phenobarbital, primidone, carbamazepine) or enzyme inhibition (valproic acid). Compared with older agents, certain new-generation AEDs offer a num-ber of pharmacokinetic advantages, particularly in terms of reduced inter-patient variability in drug clearance and a lower interaction potential. One of the most recently developed of these drugs, levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its half-life is relatively short (6 to 8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice-daily dosing regimen is adequate to produce the desired response.

Acetates↗
PubMed1995

Establishment of T-helper type 1- and T-helper type 2-like human Toxoplasma antigen-specific T-cell clones.

As an in vitro model for human cerebral toxoplasmosis, we analysed the interaction between glioblastoma cells, Toxoplasma and Toxoplasma antigen-specific T-helper cells. We established 46 different human CD4+ T-cell clones from four different donors. All T-cell clones responded to Toxoplasma antigen derived from three different Toxoplasma strains. We found that the supernatants of 44 clones induced toxoplasmostasis in glioblastoma cells. The anti-parasitic effector mechanism activated in glioblastoma cells by T-cell supernatants was the induction of the tryptophan-degrading enzyme indolamine 2,3-dioxygenase. Enzyme induction, as well as the anti-parasitic effect, was blocked by a monoclonal antibody directed against interferon-gamma (IFN-gamma), and the addition of L-tryptophan to the cultures completely blocked the anti-parasitic effect induced by T-cell supernatants. The supernatants from two of the 46 established T-cell clones (3A22 and 1A15) were unable to induce indolamine 2,3-dioxygenase activity or, as expected, toxoplasmostasis in glioblastoma cells. We further analysed the supernatants from these two clones, and found that they contained large amounts of IL-4 and no, or only limited amounts of, IFN-gamma. We therefore conclude that Toxoplasma-antigen is able to activate T-helper type 1 (Th1)- and Th2-like human T cells, and only IFN-gamma-producing cells are capable of inducing anti-parasitic effector mechanisms.

Animals↗
PubMed1979

Probable sites of action of cyclic adenosine 3',5'-monophosphate in the induction of phosphodiesterase in Dictyostelium discoideum.

The sites of action cyclic adenosine 3',5'-monophosphate (cAMP) in phosphodiesterase [EC 3.1.4.17] induction in Dictyostelium discoideum were studied. When cAMP was added to the cell suspension from the start of the incubation, the effect of the cyclic nucleotide on the cellular enzyme-induction did not appear for 30 min, then occurred abruptly. From experiments on the addition of cAMP to the cell incubation mixture at various times, preparations for the synthesis of the enzyme appear to occur during the period from 20 min to 30 min after the start of the incubation. After the addition of cycloheximide at 30 min, the enzyme was degraded very rapidly. The half-life of phosphodiesterase was roughly 21 min in the presence of cAMP, and 12 min in its absence. The degradation rates became approximately the same on removing cAMP. When daunomycin and actinomycin D were added to cells previously stimulated with cAMP, phosphodiesterase was still synthesized at a higher rate than in cells not pretreated with cAMP. These results suggest that cAMP acts at two sites at least, i.e., on enzyme synthesis at the transcription level, and in suppressing the degradation of phosphodiesterase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Phenobarbital induction and acetaminophen hepatotoxicity: resistance in the obese Zucker rodent.

The obese Zucker rodent appears to lack a significant induction response after phenobarbital pretreatment. Induction of the hepatic cytochrome P-450 system with phenobarbital is known to enhance acetaminophen hepatotoxicity. The purpose of this study was to evaluate the influence of phenobarbital enzyme induction on acetaminophen hepatotoxicity in the obese and lean Zucker rodent. A preliminary study was performed evaluating the pharmacokinetics of acetaminophen in both the obese and lean Zucker rats. Data were utilized to calculate appropriate loading doses of acetaminophen during the subsequent hepatotoxicity study. Phenobarbital enzyme-inducing regimens were administered p.o. to achieve similar steady-state phenobarbital plasma concentrations. Control rats received appropriate placebo solutions. Serum hepatic transaminase enzymes and histologic evidence of hepatocellular necrosis were utilized to evaluate hepatic damage after p.o. administration of 1300 mg of acetaminophen to both obese and lean Zucker rats. Obese Zucker control animals had approximately 2.5 times the total hepatic glutathione content compared to their lean control (164.9 +/- 43.2 vs. 65.3 +/- 18.4 mumol/whole liver). Obese Zucker animals receiving only acetaminophen showed a trend toward a reduced incidence of hepatocellular necrosis compared to similarly treated lean littermates. Obese Zucker rodents pretreated with phenobarbital had an even more pronounced resistance to acetaminophen-induced hepatocellular necrosis (P less than .01) when compared to similarly treated lean littermates. Thus, acetaminophen hepatotoxicity is reduced in the obese Zucker rat and pretreatment with phenobarbital offers further protection against hepatocellular damage. We suggest that the previously unrecognized increase in hepatic glutathione plays a major role in the resistance of the obese Zucker rat to acetaminophen hepatotoxicity.

Acetaminophen↗
PubMed1996

Effect of phenobarbital pretreatment on the pharmacokinetics and metabolism of diltiazem in rats.

In order to study the effect of cytochrome P-450 isozyme induction on the pharmacokinetics and metabolism of diltiazem (DTZ), male Sprague-Dawley rats weighing 300-600 g were randomly assigned to two groups. The enzyme induction group (n = 4) received phenobarbital 60 mg/kg i.p. once daily for 4 days, whereas the control group (n = 6) received normal saline for the same duration. Each rat then received a single oral dose of DTZ in solution (20 mg/kg). Blood samples (0.5 ml) were collected from each rat via an implanted polyethylene catheter (0.040" i.d.) in the right carotid artery at 0 (just before dosing), 0.25, 0.5, 1,2,3,4,6,8 and 10 h post-dose. Arterial plasma concentrations of DTZ and its metabolites M(A), M1, M2, M4 and M6 were determined by HPLC. Pharmacokinetics parameters were calculated using non-linear regression. The results showed that both mean Cmax and AUC of DTZ were lower (871.6 vs 79.8 ng/ml; 1171 vs 101.9 ng-h/ml), but the mean Cmax of the primary metabolites M1 and M(A) was higher after phenobarbital (M1 413.0 vs 648.9 ng/ml; M(A) 683.0 vs 814.8 ng/ml). The highest increase was seen in the mean Cmax and AUC of the secondary metabolite M2 (837.5 vs 2585.7 ng/ml; 3312.1 vs 13156.5 ng-h/ml). In contrast, plasma concentrations of the O-desmethylated metabolites M4 and M6 did not increase after phenobarbital. These results suggest that both deacetylation and N-demethylation of DTZ in rats are catalyzed by drug metabolizing enzymes inducible by phenobarbital.

Animals↗
PubMed1999

Pharmacokinetic/Pharmacodynamic models for corticosteroid receptor down-regulation and glutamine synthetase induction in rat skeletal muscle by a Receptor/Gene-mediated mechanism.

Muscle wasting and excessive fat deposition are side effects attendant to chronic corticosteroid treatment. Corticosteroid immunosuppression is necessary in circumstances such as transplantation. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was used to help elucidate the relationships between the events in the molecular cascade that result in muscle wasting and fat deposition by corticosteroids. Specifically, the relationships for receptor/gene-mediated effects that result in increased glutamine synthetase (GS) activity in skeletal muscle were quantitatively analyzed after an i.v. bolus dose of 50 mg/kg methylprednisolone in male adrenalectomized Wistar rats. Profiles of methylprednisolone pharmacokinetics, glucocorticoid receptor density, and its mRNA, GS mRNA, and GS activity in gastrocnemius muscles were determined. The results were used to develop PK/PD models using differential equations in the ADAPT II program. Two indirect response models were tested for the dynamics of glucocorticoid receptor mRNA regulation by activated steroid/receptor complex. Both reduction in message synthesis and message destabilization may be involved but with some tissue specificity. The recovery of active receptor after down-regulation is biphasic. The initial recovery may involve receptor recycling from the nucleus, whereas the later phase may involve de novo synthesis of new receptor protein. The nuclear events and GS mRNA/GS induction in rat skeletal muscle show sequential relationships for each component for corticosteroid actions. The PK/PD models provide mechanism-based methods of quantifying complex processes in receptor/gene-mediated enzyme induction featuring the characteristics of time delay and possible nonlinearity in intact tissues.

Animals↗
PubMed1990

Regulation of squalene epoxidase in HepG2 cells.

Regulation of squalene epoxidase in the cholesterol biosynthetic pathway was studied in a human hepatoma cell line, HepG2 cells. Since the squalene epoxidase activity in cell homogenates was found to be stimulated by the addition of Triton X-100, enzyme activity was determined in the presence of this detergent. Incubation of HepG2 cells for 18 h with L-654,969, a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, increased squalene epoxidase activity dose-dependently. On the other hand, low density lipoprotein (LDL) and 25-hydroxy-cholesterol decreased the enzyme activity. These results demonstrate that squalene epoxidase is regulated by the concentrations of endogenous and exogenous sterols. The affinity of the enzyme for squalene was not changed by treatment with L-654,969. Cytosolic (S105) fractions, prepared from HepG2 cells treated with or without L-654,969, had no effect on microsomal squalene epoxidase activity of HepG2 cells, in contrast to the stimulating effect of S105 fractions from rat liver homogenate. Mevalonate, LDL, and oxysterol treatment abolished the effect of L-654,969. Simultaneous addition of cycloheximide and actinomycin D also prevented enzyme induction in HepG2 cells. From these results, the change in squalene epoxidase activity is thought to be caused by the change in the amount of enzyme protein. It is further suggested that squalene epoxidase activity is suppressed only by sterols, not by nonsterol derivative(s) of mevalonate, in contrast to the regulation of HMG-CoA reductase.

Binding, Competitive↗