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PubMed1976

Control of pyrimidine biosynthesis in human lymphocytes. Inhibitory effect of guanine and guanosine on induction of enzymes for pyrimidine biosynthesis de novo in phytohemagglutinin-stimulated lymphocytes.

Human peripheral lymphocytes were incubated with Phaseolus vulgaris phytohemagglutinin. The induction of glutamine-utilizing carbamyl phosphate synthetase (EC 2.7.2.5) and aspartate transcarbamylase (EC 2.1.3.2) for pyrimidine biosynthesis de novo and the induction of uridine kinase were observed as described previously (Ito, K., and Uchino, H. (1971) J. Biol. Chem. 246, 4060-4065; Ito, K., and Uchino, H. (1973) J. Biol. Chem. 248, 389-392; Lucas, Z.J. (1967) Science 156, 1237-1240). By the addition of 1 mM guanine to the culture, the induction of the former two enzymes was inhibited, while that of uridine kinase was not, and even accelerated. An increase in the rate of [14C] bicarbonate incorporation into the acid-soluble uridine nucleotides via the de novo pathway for pyrimidine biosynthesis after phytohemagglutinin stimulation was inhibited by guanine, the incorporation rate being almost at the level of the control culture without phytohemagglutinin. Guanosine had a similar effect on pyrimidine biosynthesis. The induction of the three enzymes mentioned above was completely inhibited by adenine (1 mM). Guanine and guanosine seem to have a unique inhibitory effect on the induction of glutamine-utilizing carbamyl phosphate synthetase and aspartate transcarbamylase.

Aspartate Carbamoyltransferase↗
PubMed1975

Influence of a new virostatic compound on the induction of enzymes in rat liver.

The virostatic compound N,N-diethyl-4-[2-(2-oxo-3-tetradecyl-1-imidazolidinyl)-ethyl]-1-piperazinecarboxamide-hydrochloride (5531) was analyzed as to its effect on the induction of tryptophan-pyrrolase and tyrosineaminotransferase in rat liver. 1. The basic activity of the enzymes was not influenced by the substance either in normal or in adrenalectomized animals. 2. The induction of the enzymes by cortisone increased in the presence of the compound whereas the substrate induction remained unchanged. 3. The induction of tyrosine-aminotransferase by dexamethasonephosphate in tissue culture is inhibited if the dose of compound 5531 is higher than 5 mug/ml.

Adrenalectomy↗
PubMed1986

Diacylglycerol amplifies the induction in vivo of tyrosine aminotransferase and ornithine decarboxylase by glucocorticoid.

In adrenalectomized rats, diacylglycerol, a potent activator of protein kinase C, specifically enhanced the induction of tyrosine aminotransferase and ornithine decarboxylase by even maximally effective doses of dexamethasone phosphate, but itself had no effect on these enzyme inductions in the absence of glucocorticoid. The amplifications of enzyme induction by diacylglycerol was dose-dependent and the time courses of the amplified inductions were similar to those of the inductions by dexamethasone phosphate alone. Since diacylglycerol did not affect the induction of these enzymes by glucagon and insulin, its amplifying effect seemed to be specific for induction by glucocorticoids.

Adrenalectomy↗
PubMed1984

Phenobarbital in the genetically obese Zucker rat. I. Pharmacokinetics after acute and chronic administration.

The pharmacokinetics of the enzyme inducer, phenobarbital, was evaluated in genetically obese and lean Zucker and lean Sprague-Dawley rats. The volume of distribution of phenobarbital in obese Zucker rats was larger (0.416 liter) than for lean Zucker (0.299 liter) or Sprague-Dawley rats (0.312 liter). Standardizing the volume of distribution for total body weight in the obese and lean Zucker and lean Sprague-Dawley rats resulted in similar volume terms. Intra- and inter-strain differences in phenobarbital clearance were observed between the obese and lean Zucker (11.9 and 14.1 ml/hr, respectively) and lean Sprague-Dawley rats (23.0 ml/hr). Greater differences in phenobarbital clearance were observed when clearance was corrected for body weight. Whether comparing the absolute or standardized pharmacokinetic data, lean and obese Zucker rats will exhibit 2- to 3-fold higher phenobarbital plasma concentrations after administration of a standard 75- to 100-mg/kg enzyme-inducing regimen relative to Sprague-Dawley rats. Pharmacokinetic parameters from the single dose study were used to calculate appropriate phenobarbital doses (21-58 mg/kg/12 hr) to achieve similar steady-state phenobarbital plasma concentrations after chronic oral administration in all three groups of rats. Steady-state phenobarbital clearance values were not significantly different from clearance values after single dose administration in each group of rats. The dramatic intra- and inter-strain alterations in phenobarbital disposition demonstrated in this study explain the high mortality reported in Zucker rats after administration of traditional enzyme induction doses of phenobarbital. Differences in phenobarbital disposition should be considered in enzyme induction studies.

Animals↗
PubMed1966

Studies on the mechanism of hormonal induction of alkaline phosphatase in human cell cultures. I. Effects of puromycin and actinomycin D.

Increased alkaline phosphatase activity is induced in certain epithelial cell cultures by hormones with adrenal glucocorticoid activity or their analogues such as prednisolone (Delta(I)-hydrocortisone). Enzyme induction occurs in two distinct phases. During the first 12 hr after the addition of prednisolone, there is a small increase in alkaline phosphatase levels. After 15 to 24 hr, the enzyme activity shows a sudden, marked linear rise, reaching a maximum at 60 to 80 hr. Puromycin blocks enzyme induction immediately, even when added during the period of rapid increase of enzyme. Actinomycin D blocks induction when added no later than 8 hr after the addition of prednisolone. On the other hand, Actinomycin D added during the phase of rapid enzyme induction has no effect for at least 12 hr. These findings suggest that de novo protein synthesis is involved in prednisolone induction of alkaline phosphatase and that the RNA messenger for this enzyme is relatively stable.

Cell Division↗
PubMedDate not supplied

Regional induction of CYP1A1 in rat liver following treatment with mixtures of PCB 126 and PCB 153.

Liver enzyme induction has been shown previously to be regional with clear borders between induced and uninduced regions in vivo, and cells either fully induced or not induced in vitro. The current study examined this phenomenon in vivo by evaluating enzyme induction after exposure to PCB 126 and PCB 153 in female Fisher 344 (F344) and male Sprague-Dawley (SD) rats. IHC revealed a regional induction of CYP1A1 after exposure to PCB 126, apparent in the centrilobular region at lower doses and progressing to panlobular with higher doses. PCB 153 exposure induced CYP2B1/2 in the centrilobular region, which spread to the midzonal region as the dose increased, but never became panlobular even at the highest dosage tested. In rats treated with PCB 126 in combination with high doses of PCB 153, induction of CYP1A1 occurred preferentially in the periportal region, a reversal from the pattern seen with PCB 126 alone. This CYP1A1 induction pattern reversal is a unique example of complex biological interactions between coplanar (PCB 126) and noncoplanar (PCB 153) halogenated aromatic hydrocarbons.

Animals↗
PubMed1995

Effect of nifedipine, verapamil and diltiazem on the enzyme-inducing activity of phenobarbital and beta-naphthoflavone.

1. The effects of three calcium antagonists (CA), nifedipine (NF), verapamil (V) and diltiazem (DL) on the enzyme-inducing activity of phenobarbital (PB) and beta-naphthoflavone (beta-NF) were measured by hexobarbital (HB) sleeping time, benzphetamine-N-demethylase (BND) ethoxycourmarin-O-deethylase (ECOD) and ethoxyresorufin-O-deethylase (EROD) activities, as well as by the cytochrome P-450 and cytochrome b5 content. 2. NF, V and DL at oral doses of 100, 80 and 60 mg/kg administered 1 hr before PB additionally shortened the HB sleeping time. 3. Single administration of calcium antagonists on the background of developed PB-provoked enzyme induction prolonged the PB-shortened hexobarbital sleeping time. 4. Three day administration of NF, V and DL plus PB slightly decreased the enzyme-inducing effect of PB on BND activity and cytochrome P-450 and cytochrome b5 content. 5. NF and V administered only once after PB-provoked enzyme induction increased the PB enzyme-inducing effect on BND activity and on the content of cytochrome P-450. DL decreased the PB-induced BND activity and cytochrome P-450 and cytochrome b5 content. 6. The calcium antagonists studied affected the enzyme-inducing activity of beta-NF to a lesser extent when compared to PB. Only NF was found to potentiate the enzyme-inducing effect of beta-NF on the EROD activity and on the cytochrome P-450 content.

Animals↗
PubMed1991

Pretreatment with a nontoxic derivative of endotoxin induces functional protection against cardiac ischemia/reperfusion injury.

We hypothesized that low-dose pretreatment of an intact animal with a nontoxic derivative of endotoxin, monophosphoryl lipid A (MPL), would induce protection against cardiac ischemia/reperfusion (I/R) injury. The purposes of this study were to investigate whether MPL pretreatment would induce functional protection against cardiac I/R injury, to delineate the temporal induction of protection, and to examine antioxidant enzyme induction as a mechanism of protection. Rats were administered a 5 mg/kg dose of MPL at 2 hours and 24 hours before a 25-minute, global, 37 degrees C ischemic insult followed by reperfusion (modified Langendorff). At 40 minutes of reperfusion, ventricular function was assessed (ventricular balloon; developed pressure, rate of contraction, rate of relaxation). Hearts from rats pretreated with MPL 24 hours before isolation exhibited preservation of ventricular function (p less than 0.05). After I/R, hearts from rats pretreated with MPL 24 hours before isolation had increased (p less than 0.05) catalase activity compared to saline pretreated controls and rats pretreated with MPL 2 hours before isolation. We conclude that (1) pretreatment with MPL induces functional protection against cardiac I/R injury, (2) protection (not evident at 2 hours) is maximal at 24 hours, suggesting enzyme induction, and (3) increased catalase activity correlates with the functional protection.

Analysis of Variance↗
PubMed1988

The use of primary cultures of adult rat hepatocytes to study induction of enzymes and DNA synthesis: effect of nafenopin and electroporation.

Primary cultures of adult rat hepatocytes maintained in a well-differentiated state, in a chemically defined medium containing 2% DMSO, have been utilized to study the effect of non-mutagenic hepatocarcinogens such as the peroxisome proliferator nafenopin. The parameters chosen in this in vitro system were those that paralleled the major in vivo effects of nafenopin on the liver, mainly: the proliferation of the endoplasmic reticulum and induction of cytochrome P-452, the proliferation of the peroxisome compartment and the induction of cyanide-insensitive beta-oxidation of fatty acids and the stimulation of liver growth as measured by the DNA synthetic activity of the hepatocytes. In this review, we also describe the morphology of hepatocyte cultures prepared from previously electroporated hepatocytes and the potential for the use of electroporation to introduce growth related genes into hepatocyte cells to study the mechanisms of hepatocyte growth at the molecular level. In addition we describe the formation of endoplasmic reticulum whorls in these cultures as a consequence of nafenopin treatment. 'Whorl formation' by hepatotrophic chemicals has been previously shown to occur in vivo; in this report, it is described for the first time in vitro.

Animals↗
PubMed1986

Further investigations of race:cultivar-specific induction of enzymes related to phytoalexin biosynthesis in soybean roots following infection with Phytophthora megasperma f.sp. glycinea.

The activities of the following enzymes in soybean roots were determined at early times after infection of the roots with zoospores of an incompatible or a compatible race of Phytophthora megasperma f.sp. glycinea: dimethylallyl-diphosphate : 3,6a,9-trihydroxypterocarpan dimethylallyltransferase (prenyltransferase), an enzyme specific for glyceollin biosynthesis; NADPH-cytochrome reductase and hydroxymethylglutaryl-CoA reductase, enzymes related to the glyceollin pathway; and isocitrate dehydrogenase. Already at 4 h after infection there was a higher activity of the prenyltransferase in the incompatible interaction than in the compatible interaction, and enzyme activity in the incompatible interaction increased considerably between 4 and 8 h after infection. In the compatible interaction prenyltransferase activity was only slightly higher than in uninfected roots. The activity of the other enzymes in infected roots was not significantly different from that in the uninfected roots. No qualitative differences could be detected between the two-dimensional patterns of unlabelled proteins or proteins labelled with L-[35S]methionine of infected and uninfected roots at early times after infection. We conclude from these and earlier results (A. Bonhoff et al. (1986) Arch. Biochem. Biophys. 246, 149-154) that infection of the soybean roots with an incompatible race of the fungus leads to selective induction of the phytoalexin pathway and presumably to induction of other as yet unknown defense mechanisms.

Buffers↗
PubMed2004

Sugar and fructan accumulation during metabolic adjustment between respiration and fermentation under low oxygen conditions in wheat roots.

In terms of gene expression and carbohydrate metabolism, the response of wheat seedlings to hypoxia is dramatically different from the anoxic response. Total carbohydrate content of roots increased 4-fold during 6 days of hypoxia, with a 17-fold increase in fructans. In contrast, anoxically treated roots depleted all soluble carbohydrates and died within 72 h. Gas exchange measurements (CO(2) release vs. O(2) uptake) demonstrate that hypoxia establishes a new balance between fermentation and aerobic respiration in the roots without altering the flux of carbon through glycolysis. Furthermore, the respiratory component of this new balance is 55% higher in roots that have been hypoxically pretreated compared to non-hypoxically pretreated roots. The establishment of this new homeostasis under hypoxia involves the induction of glycolytic (aldolase and enolase) and fermentative enzymes (pyruvate decarboxylase, alcohol dehydrogenase, and lactate dehydrogenase). Enzyme induction is generally complete within 24 h with mRNA induction occurring primarily during Period I (0-6 h of hypoxia), and maximal enzymes activities attained during Period II (6-24 h of hypoxia). Accumulation rates of Suc, hexoses, and fructans also change during Periods I and II. By the start of Period III (24-144 h of hypoxia), the metabolic adjustments are complete and fructans are the major carbohydrate accumulated. In anoxia, the pattern of enzyme induction was dramatically different: aldolase was not induced and declined throughout the treatment. Alcohol dehydrogenase, pyruvate decarboxylase, and lactate dehydrogenase were induced as in hypoxia, but rapidly declined within 72 h of anoxia. Only enolase exhibited a similar expression pattern in both anoxia and hypoxia.

Journal Article↗
PubMed1984

Cultured hepatoma cells for the study of enzyme regulation: induction of ornithine decarboxylase by insulin and asparagine.

The induction and decay of ornithine decarboxylase (ODC) by insulin and asparagine in cultures of H4-II-EC3 (H35) hepatoma cells was studied in a modified Waymouth medium in the presence of fetal bovine serum (FBS) and in serum-free media. The insulin response was enhanced by the presence of asparagine although the effect of asparagine was not so much on the initial increase as it was on a slowing of the decline after the maximum was reached at 6 to 8 h after the supplements were added together with fresh medium. In all cases the initial ODC activity was zero at zero time for addition of media and supplements, and, after reaching the maximum, activity declined to near zero by 24 h. Fetal bovine serum gave induction that followed a similar time course but was inferior to the combination of insulin plus asparagine and, in fact, FBS inhibited the latter response. Putrescine (the product formed from ornithine by ODC), at 10(-5) M, markedly inhibited the induction of ODC by insulin or FBS, but the inhibition was less when asparagine was present.

Animals↗
PubMed1985

The pathologic response of the liver and thyroid of the rat to potassium prorenoate (SC-23992).

A 3-month dose range finding study in preparation for a 2-yr carcinogenicity study of potassium prorenoate (SC-23992), a steroid with an antihypertensive profile, is reported. The drug was administered by gavage once daily at doses of 10, 30, and 100 mg/kg/day to Charles River CD rats. Treatment was terminated at 13 weeks and 10 randomly selected animals from each treatment group were killed and necropsied. The remaining 10 animals in each dose group, including controls, were maintained for an additional 4 weeks, in order to investigate reversibility of changes, and then were killed and necropsied. Dose-related increases in thyroid-stimulating hormone (TSH) levels were observed in treated animals of both sexes during the dosing period and the changes were statistically significant and correlated with an increased thyroid weight in females at 13 weeks. Dose-related morphologic changes in the thyroid, observed by light and electron microscopy, were compatible with the effects of TSH stimulation. Liver weights, which increased, were dose-related. In females the increase was statistically significant at the high dose at 2, 4, and 13 weeks. In males it was significant at the high dose at 13 weeks. Microsomal enzyme levels were increased in a time- and dose-related manner with higher values in females than in males. The pattern of enzyme induction was of the type exemplified by pregnenolone- 16-alpha-carbonitrile. Morphologic changes in the liver showed centrilobular hepatocyte enlargement with smooth endoplasmic reticulum membrane proliferation confirmed by electron microscopy. All positive findings returned to normal after the 4-week treatment-free period. The relationship between the thyroid stimulation to liver enzyme induction is of interest. Evidence is presented here that in the presence of SC-23992, TSH stimulation and liver enzyme induction occurred. The possibility that the liver metabolism stimulates the thyroid T3, T4 elimination with secondary TSH activity is a possible explanation, but on the basis of existing information, direct action by SC-23992 on the thyroid cannot be excluded.

Animals↗
PubMed1976

Regulatory properties of an inducible aliphatic amidase in a thermophilic bacillus.

A thermophilic bacillus growing on acetamide as both carbon and nitrogen sources produces an inducible amidase. This amidase hydrolysed the following amides in decreasing order or activity, in comparison with acetamide (1.00): propionamide (0.97), fluoroacetamide (0.84), formamide (0.35) and glycinamide (0.12). Cyanoacetamide, dimethylacetamide, dimethylformamide and urea also induced the synthesis of the amidase, but were not substrates of the enzyme. Studies with protoplasts suggest that the amidase is located in the cytoplasm. Glucose strongly inhibited amidase synthesis; and limiting nitrogen did not release this inhibition. Urea strongly inhibited amidase activity in a competitive manner; but the inhibition caused by iodoacetamide and cyanoacetamide was non-competitive. Both thioacetamide and thiourea were effective inhibitors of enzyme induction. Bacteria grown on a succinate-minimal medium exhibited a lag in amidase synthesis, which could be eliminated by decreasing the concentration of succinate. Acetate- or pyruvate-grown cultures behaved similarly, while those grown on alanine or glutamate exhibited no lag in enzyme induction. In the mutant strain E21, repression of amidase synthesis by glucose was much less evident and no lag for induction was apparent with any of the other carbon sources mentioned.

Acetamides↗
PubMed1997

Development of a monoclonal antibody to 6 beta-hydroxycortisol and its application in an enzyme-linked immunosorbent assay (ELISA) for 6 beta-hydroxycortisol in urine.

A novel monoclonal antibody to 6 beta-hydroxycortisol (6 beta-OHC) was generated and incorporated into an antigen-coated indirect enzyme-linked immunosorbent assay (ELISA) using 6 beta-OHC-protein conjugate as the steroid-coating antigen. The monoclonal antibody is specific to 6 beta-OHC and 6 beta-OHC-3-carboxymethyloxime. Cross-reactivity with other structurally related steroids such as cortisol, cortisone, and 6 beta-hydroxycortisone was less than 10%. Two different clones (clone 5C1 and 19F) of the monoclonal anti-6 beta-OHC antibody have been developed, each with slightly different sensitivity and specificity. The sensitivity of the MAb clones was not significantly improved when compared to the rabbit polyclonal antibodies in this study, but still within the accepted detection limit for 6 beta-OHC in both human and laboratory animals. The assay had a detection limit of 200 ng/ml, an intraassay variation of 6.4% and an interassay variation of 7.3%. The application of the anti-6 beta-OHC-MAb-based-ELISA was tested by measuring the urinary output of 6 beta-OHC in human before and after enzyme induction by rifampicin treatment. The mean 24-h urine output of 6 beta-OHC in human subjects was 485 +/- 100 micrograms and 1478 +/- 281 micrograms before and after rifampicin administration, respectively. In conclusion, the monoclonal anti-6 beta-OHC antibody developed in this study has the required specificity and sensitivity as an alternative method for measuring urinary 6 beta-OHC in the detection of enzyme induction or enzyme inhibition of CYP3A in humans and laboratory animals.

Adult↗
PubMed2001

Induction of cytochrome P450 2B1 by pyrethroids in primary rat hepatocyte cultures.

Numerous xenobiotics are capable of inducing their own metabolism and by enzyme induction can also lead to enhanced biotransformation of other xenobiotics. In this project, we examined the influence of pyrethroids (permethrin, cypermethrin, and fenvalerate) on the expression and activity of the phenobarbital (PB)-inducible cytochrome P450 2B1 isoform (CYP2B1) in primary rat hepatocyte cultures. Incubation of hepatocyte cultures with pyrethroids resulted in a marked CYP2B1 induction. Among the tested pyrethroids, permethrin elicited the most pronounced induction of CYP2B1 mRNA, which exceeded maximal induction achieved by PB at concentrations approximately 10-fold higher. Furthermore, permethrin induced CYP3A1 mRNA expression, while the expression of the CYP1A1 isoform, which in vivo is not responsive to PB treatment, was not significantly affected by pyrethroids. Permethrin-dependent enhancement of CYP2B1 and CYP3A1 mRNA expression was repressed by the hepatotrophic cytokine epidermal growth factor, which is known to also inhibit PB-dependent induction of CYP2B1. Several metabolites of permethrin formed by hepatocytes (3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid, 3-phenoxybenzyl alcohol, and 3-phenoxybenzoic acid) were ineffective in inducing CYP2B1 mRNA. Furthermore, permethrin stimulated the expression of the luciferase reporter gene under control of the CYP2B1 promoter (comprising the PB-responsive enhancer module) in transiently transfected primary hepatocyte cultures. Thus, permethrin-stimulated gene expression occurred on the transcriptional level. Taken together, these results indicate that the pyrethroid permethrin is a PB-like inducer. Due to its superior potency in induction, permethrin appears as a useful substance for mechanistic studies to elucidate the mechanism of enzyme induction by phenobarbital.

Animals↗
PubMed1983

Induction of proteinases in Legionella by growth on agar containing serum.

Non-proliferating cells of Legionella show a rather small proteolytic action on human serum proteins. However, if the strains grow on agar plates containing serum the proteolysis is very strong. This effect may be due to an induction of the appropriate enzymes by their substrates. The alterations of 24 investigated proteins demonstrated by immunoelectrophoresis show anodic shifts of bands and their disappearance (Table 1, Fig. 1-15). The shifted proteins are not degraded significantly. Their altered electrophoretic mobility may be due to a change of electrical charge by loss of one or a few end standing amino acids. The disappearance of bands in the immunoelectrophoretic assay and the simultaneous diminution of the protein concentration measured by the method of immunodiffusion suggests a proteolysis (Table 2). No inhibitory effect of the proteinase inhibitor aprotinin could be observed. The results suggest that the extent of the enzyme induction may be decisive for the virulence of a strain.

Agar↗
PubMed1984

The effect of phenobarbitone pre-treatment on vitamin K1 disposition in the rat and rabbit.

The effect of phenobarbitone enzyme induction on the pharmacokinetics of an intravenous pharmacological dose (1 mg/kg) of vitamin K1 was studied in the rabbit. Phenobarbitone pretreatment significantly (P less than 0.01) increased the plasma clearance of vitamin K1 and decreased the terminal (beta) half-life from 2.08 +/- 0.56 to 0.99 +/- 0.30 hr. However, phenobarbitone pretreatment did not alter the pharmacodynamic response to vitamin K1 measured as the increase in prothrombin complex activity, in brodifacoum-anticoagulated rabbits. In the rat, phenobarbitone enzyme induction increased the extent and rate of biliary excretion of polar vitamin K1 metabolites following intravenous administration of the vitamin. Perturbation of vitamin K1 metabolism by phenobarbitone enzyme induction is not dependent on the concentration of the vitamin. The greater hepatic elimination resulted in lower systemic blood concentrations of both vitamin K1 and the 2,3-epoxide. A similar reduction in the concentration of vitamin K1 in the blood of epileptic mothers treated with anticonvulsants such as phenobarbitone may explain the coagulation defect frequently observed in their offspring [K. R. Mountain, J. Hirsh and A.S. Gallus, Lancet ii, 265 (1970)].

Animals↗